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Search: WFRF:(Schwartz Yuri B)

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1.
  • Chen, L. -J, et al. (author)
  • Electron Bulk Acceleration and Thermalization at Earth's Quasiperpendicular Bow Shock
  • 2018
  • In: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 120:22
  • Journal article (peer-reviewed)abstract
    • Electron heating at Earth's quasiperpendicular bow shock has been surmised to be due to the combined effects of a quasistatic electric potential and scattering through wave-particle interaction. Here we report the observation of electron distribution functions indicating a new electron heating process occurring at the leading edge of the shock front. Incident solar wind electrons are accelerated parallel to the magnetic field toward downstream, reaching an electron-ion relative drift speed exceeding the electron thermal speed. The bulk acceleration is associated with an electric field pulse embedded in a whistler-mode wave. The high electron-ion relative drift is relaxed primarily through a nonlinear current-driven instability. The relaxed distributions contain a beam traveling toward the shock as a remnant of the accelerated electrons. Similar distribution functions prevail throughout the shock transition layer, suggesting that the observed acceleration and thermalization is essential to the cross-shock electron heating. 
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2.
  • Ergun, R. E., et al. (author)
  • Magnetospheric Multiscale observations of large-amplitude, parallel, electrostatic waves associated with magnetic reconnection at the magnetopause
  • 2016
  • In: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 43:11, s. 5626-5634
  • Journal article (peer-reviewed)abstract
    • We report observations from the Magnetospheric Multiscale satellites of large-amplitude, parallel, electrostatic waves associated with magnetic reconnection at the Earth's magnetopause. The observed waves have parallel electric fields (E-||) with amplitudes on the order of 100mV/m and display nonlinear characteristics that suggest a possible net E-||. These waves are observed within the ion diffusion region and adjacent to (within several electron skin depths) the electron diffusion region. They are in or near the magnetosphere side current layer. Simulation results support that the strong electrostatic linear and nonlinear wave activities appear to be driven by a two stream instability, which is a consequence of mixing cold (<10eV) plasma in the magnetosphere with warm (similar to 100eV) plasma from the magnetosheath on a freshly reconnected magnetic field line. The frequent observation of these waves suggests that cold plasma is often present near the magnetopause.
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3.
  • Eriksson, S., et al. (author)
  • Magnetospheric Multiscale observations of magnetic reconnection associated with Kelvin-Helmholtz waves
  • 2016
  • In: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 43:11, s. 5606-5615
  • Journal article (peer-reviewed)abstract
    • The four Magnetospheric Multiscale (MMS) spacecraft recorded the first direct evidence of reconnection exhausts associated with Kelvin-Helmholtz (KH) waves at the duskside magnetopause on 8 September 2015 which allows for local mass and energy transport across the flank magnetopause. Pressure anisotropy-weighted Walen analyses confirmed in-plane exhausts across 22 of 42 KH-related trailing magnetopause current sheets (CSs). Twenty-one jets were observed by all spacecraft, with small variations in ion velocity, along the same sunward or antisunward direction with nearly equal probability. One exhaust was only observed by the MMS-1,2 pair, while MMS-3,4 traversed a narrow CS (1.5 ion inertial length) in the vicinity of an electron diffusion region. The exhausts were locally 2-D planar in nature as MMS-1,2 observed almost identical signatures separated along the guide-field. Asymmetric magnetic and electric Hall fields are reported in agreement with a strong guide-field and a weak plasma density asymmetry across the magnetopause CS.
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4.
  • Gingell, I, et al. (author)
  • Observations of Magnetic Reconnection in the Transition Region of Quasi-Parallel Shocks
  • 2019
  • In: Geophysical Research Letters. - : AMER GEOPHYSICAL UNION. - 0094-8276 .- 1944-8007. ; 46:3, s. 1177-1184
  • Journal article (peer-reviewed)abstract
    • Using observations of Earth's bow shock by the Magnetospheric Multiscale mission, we show for the first time that active magnetic reconnection is occurring at current sheets embedded within the quasi-parallel shock's transition layer. We observe an electron jet and heating but no ion response, suggesting we have observed an electron-only mode. The lack of ion response is consistent with simulations showing reconnection onset on sub-ion time scales. We also discuss the impact of electron heating in shocks via reconnection.
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5.
  • Gingell, I., et al. (author)
  • Statistics of Reconnecting Current Sheets in the Transition Region of Earth's Bow Shock
  • 2020
  • In: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 125:1
  • Journal article (peer-reviewed)abstract
    • We have conducted a comprehensive survey of burst mode observations of Earth's bow shock by the Magnetospheric Multiscale mission to identify and characterize current sheets associated with collisionless shocks, with a focus on those containing fast electron outflows, a likely signature of magnetic reconnection. The survey demonstrates that these thin current sheets are observed within the transition region of approximately 40% of shocks within the burst mode data set of Magnetospheric Multiscale. With only small apparent bias toward quasi-parallel shock orientations and high Alfven Mach numbers, the results suggest that reconnection at shocks is a universal process, occurring across all shock orientations and Mach numbers. On examining the distributions of current sheet properties, we find no correlation between distance from the shock, sheet width, or electron jet speed, though the relationship between electron and ion jet speed supports expectations of electron-only reconnection in the region. Furthermore, we find that robust heating statistics are not separable from background fluctuations, and thus, the primary consequence of reconnection at shocks is in relaxing the topology of the disordered magnetic field in the transition region.
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6.
  • Johlander, Andreas, et al. (author)
  • Rippled Quasiperpendicular Shock Observed by the Magnetospheric Multiscale Spacecraft
  • 2016
  • In: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 117:16
  • Journal article (peer-reviewed)abstract
    • Collisionless shock nonstationarity arising from microscale physics influences shock structure and particle acceleration mechanisms. Nonstationarity has been difficult to quantify due to the small spatial and temporal scales. We use the closely spaced (subgyroscale), high-time-resolution measurements from one rapid crossing of Earth's quasiperpendicular bow shock by the Magnetospheric Multiscale (MMS) spacecraft to compare competing nonstationarity processes. Using MMS's high-cadence kinetic plasma measurements, we show that the shock exhibits nonstationarity in the form of ripples.
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7.
  • Lavraud, B., et al. (author)
  • Currents and associated electron scattering and bouncing near the diffusion region at Earth's magnetopause
  • 2016
  • In: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 43:7, s. 3042-3050
  • Journal article (peer-reviewed)abstract
    • Based on high-resolution measurements from NASA's Magnetospheric Multiscale mission, we present the dynamics of electrons associated with current systems observed near the diffusion region of magnetic reconnection at Earth's magnetopause. Using pitch angle distributions (PAD) and magnetic curvature analysis, we demonstrate the occurrence of electron scattering in the curved magnetic field of the diffusion region down to energies of 20 eV. We show that scattering occurs closer to the current sheet as the electron energy decreases. The scattering of inflowing electrons, associated with field-aligned electrostatic potentials and Hall currents, produces a new population of scattered electrons with broader PAD which bounce back and forth in the exhaust. Except at the center of the diffusion region the two populations are collocated and appear to behave adiabatically: the inflowing electron PAD focuses inward (toward lower magnetic field), while the bouncing population PAD gradually peaks at 90 degrees away from the center (where it mirrors owing to higher magnetic field and probable field-aligned potentials).
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8.
  • Wilder, F. D., et al. (author)
  • The nonlinear behavior of whistler waves at the reconnecting dayside magnetopause as observed by the Magnetospheric Multiscale mission : A case study
  • 2017
  • In: Journal of Geophysical Research - Space Physics. - : Blackwell Publishing Ltd. - 2169-9380 .- 2169-9402. ; 122:5, s. 5487-5501
  • Journal article (peer-reviewed)abstract
    • We show observations of whistler mode waves in both the low-latitude boundary layer (LLBL) and on closed magnetospheric field lines during a crossing of the dayside reconnecting magnetopause by the Magnetospheric Multiscale (MMS) mission on 11 October 2015. The whistlers in the LLBL were on the electron edge of the magnetospheric separatrix and exhibited high propagation angles with respect to the background field, approaching 40°, with bursty and nonlinear parallel electric field signatures. The whistlers in the closed magnetosphere had Poynting flux that was more field aligned. Comparing the reduced electron distributions for each event, the magnetospheric whistlers appear to be consistent with anisotropy-driven waves, while the distribution in the LLBL case includes anisotropic backward resonant electrons and a forward resonant beam at near half the electron-Alfvén speed. Results are compared with the previously published observations by MMS on 19 September 2015 of LLBL whistler waves. The observations suggest that whistlers in the LLBL can be both beam and anisotropy driven, and the relative contribution of each might depend on the distance from the X line.
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9.
  • Araç, Demet, et al. (author)
  • Dissecting signaling and functions of adhesion G protein-coupled receptors
  • 2012
  • In: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1276:1, s. 1-25
  • Journal article (peer-reviewed)abstract
    • G protein-coupled receptors (GPCRs) comprise an expanded superfamily of receptors in the human genome. Adhesion class G protein-coupled receptors (adhesion-GPCRs) form the second largest class of GPCRs. Despite the abundance, size, molecular structure, and functions in facilitating cell and matrix contacts in a variety of organ systems, adhesion-GPCRs are by far the most poorly understood GPCR class. Adhesion-GPCRs possess a unique molecular structure, with extended N-termini containing various adhesion domains. In addition, many adhesion-GPCRs are autoproteolytically cleaved into an N-terminal fragment (NTF, NT, α-subunit) and C-terminal fragment (CTF, CT, β-subunit) at a conserved GPCR autoproteolysis-inducing (GAIN) domain that contains a GPCR proteolysis site (GPS). These two features distinguish adhesion-GPCRs from other GPCR classes. Though active research on adhesion-GPCRs in diverse areas, such as immunity, neuroscience, and development and tumor biology has been intensified in the recent years, the general biological and pharmacological properties of adhesion-GPCRs are not well known, and they have not yet been used for biomedical purposes. The "6th International Adhesion-GPCR Workshop," held at the Institute of Physiology of the University of Würzburg on September 6-8, 2012, assembled a majority of the investigators currently actively pursuing research on adhesion-GPCRs, including scientists from laboratories in Europe, the United States, and Asia. The meeting featured the nascent mechanistic understanding of the molecular events driving the signal transduction of adhesion-GPCRs, novel models to evaluate their functions, and evidence for their involvement in human disease.
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10.
  • Ergun, R. E., et al. (author)
  • Magnetospheric Multiscale Satellites Observations of Parallel Electric Fields Associated with Magnetic Reconnection
  • 2016
  • In: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 116:23
  • Journal article (peer-reviewed)abstract
    • We report observations from the Magnetospheric Multiscale satellites of parallel electric fields (E-vertical bar vertical bar) associated with magnetic reconnection in the subsolar region of the Earth's magnetopause. E-vertical bar vertical bar events near the electron diffusion region have amplitudes on the order of 100 mV/m, which are significantly larger than those predicted for an antiparallel reconnection electric field. This Letter addresses specific types of E-vertical bar vertical bar events, which appear as large-amplitude, near unipolar spikes that are associated with tangled, reconnected magnetic fields. These E-vertical bar vertical bar events are primarily in or near a current layer near the separatrix and are interpreted to be double layers that may be responsible for secondary reconnection in tangled magnetic fields or flux ropes. These results are telling of the three-dimensional nature of magnetopause reconnection and indicate that magnetopause reconnection may be often patchy and/or drive turbulence along the separatrix that results in flux ropes and/or tangled magnetic fields.
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11.
  • Hamann, Joerg, et al. (author)
  • International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors
  • 2015
  • In: Pharmacological Reviews. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0031-6997 .- 1521-0081. ; 67:2, s. 338-367
  • Research review (peer-reviewed)abstract
    • The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential.
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12.
  • Ho, Joshua W. K., et al. (author)
  • Comparative analysis of metazoan chromatin organization
  • 2014
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 512:7515, s. 449-U507
  • Journal article (peer-reviewed)abstract
    • Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms(1-3). Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths(4,5). To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.
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13.
  • Kang, Hyuckjoon, et al. (author)
  • Variant Polycomb complexes in Drosophila consistent with ancient functional diversity
  • 2022
  • In: Science Advances. - : NLM (Medline). - 2375-2548. ; 8:36
  • Journal article (peer-reviewed)abstract
    • Polycomb group (PcG) mutants were first identified in Drosophila on the basis of their failure to maintain proper Hox gene repression during development. The proteins encoded by the corresponding fly genes mainly assemble into one of two discrete Polycomb repressive complexes: PRC1 or PRC2. However, biochemical analyses in mammals have revealed alternative forms of PRC2 and multiple distinct types of noncanonical or variant PRC1. Through a series of proteomic analyses, we identify analogous PRC2 and variant PRC1 complexes in Drosophila, as well as a broader repertoire of interactions implicated in early development. Our data provide strong support for the ancient diversity of PcG complexes and a framework for future analysis in a longstanding and versatile genetic system.
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14.
  • Misulovin, Ziva, et al. (author)
  • Association of cohesin and Nipped-B with transcriptionally active regions of the Drosophila melanogaster genome
  • 2008
  • In: Chromosoma. - : Springer Science and Business Media LLC. - 0009-5915 .- 1432-0886. ; 117:1, s. 89-102
  • Journal article (peer-reviewed)abstract
    • The cohesin complex is a chromosomal component required for sister chromatid cohesion that is conserved from yeast to man. The similarly conserved Nipped-B protein is needed for cohesin to bind to chromosomes. In higher organisms, Nipped-B and cohesin regulate gene expression and development by unknown mechanisms. Using chromatin immunoprecipitation, we find that Nipped-B and cohesin bind to the same sites throughout the entire non-repetitive Drosophila genome. They preferentially bind transcribed regions and overlap with RNA polymerase II. This contrasts sharply with yeast, where cohesin binds almost exclusively between genes. Differences in cohesin and Nipped-B binding between Drosophila cell lines often correlate with differences in gene expression. For example, cohesin and Nipped-B bind the Abd-B homeobox gene in cells in which it is transcribed, but not in cells in which it is silenced. They bind to the Abd-B transcription unit and downstream regulatory region and thus could regulate both transcriptional elongation and activation. We posit that transcription facilitates cohesin binding, perhaps by unfolding chromatin, and that Nipped-B then regulates gene expression by controlling cohesin dynamics. These mechanisms are likely involved in the etiology of Cornelia de Lange syndrome, in which mutation of one copy of the NIPBL gene encoding the human Nipped-B ortholog causes diverse structural and mental birth defects.
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15.
  • Stawarz, J. E., et al. (author)
  • Observations of turbulence in a Kelvin-Helmholtz event on 8 September 2015 by the Magnetospheric Multiscale mission
  • 2016
  • In: Journal of Geophysical Research - Space Physics. - : Blackwell Publishing. - 2169-9380 .- 2169-9402. ; 121:11, s. 11021-11034
  • Journal article (peer-reviewed)abstract
    • Spatial and high-time-resolution properties of the velocities, magnetic field, and 3-D electric field within plasma turbulence are examined observationally using data from the Magnetospheric Multiscale mission. Observations from a Kelvin-Helmholtz instability (KHI) on the Earth's magnetopause are examined, which both provides a series of repeatable intervals to analyze, giving better statistics, and provides a first look at the properties of turbulence in the KHI. For the first time direct observations of both the high-frequency ion and electron velocity spectra are examined, showing differing ion and electron behavior at kinetic scales. Temporal spectra exhibit power law behavior with changes in slope near the ion gyrofrequency and lower hybrid frequency. The work provides the first observational evidence for turbulent intermittency and anisotropy consistent with quasi two-dimensional turbulence in association with the KHI. The behavior of kinetic-scale intermittency is found to have differences from previous studies of solar wind turbulence, leading to novel insights on the turbulent dynamics in the KHI.
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16.
  • Wilder, F. D., et al. (author)
  • Observations of large-amplitude, parallel, electrostatic waves associated with the Kelvin-Helmholtz instability by the magnetospheric multiscale mission
  • 2016
  • In: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 43:17, s. 8859-8866
  • Journal article (peer-reviewed)abstract
    • On 8 September 2015, the four Magnetospheric Multiscale spacecraft encountered a Kelvin-Helmholtz unstable magnetopause near the dusk flank. The spacecraft observed periodic compressed current sheets, between which the plasma was turbulent. We present observations of large-amplitude (up to 100 mV/m) oscillations in the electric field. Because these oscillations are purely parallel to the background magnetic field, electrostatic, and below the ion plasma frequency, they are likely to be ion acoustic-like waves. These waves are observed in a turbulent plasma where multiple particle populations are intermittently mixed, including cold electrons with energies less than 10 eV. Stability analysis suggests a cold electron component is necessary for wave growth.
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17.
  • Wilder, F. D., et al. (author)
  • Observations of whistler mode waves with nonlinear parallel electric fields near the dayside magnetic reconnection separatrix by the Magnetospheric Multiscale mission
  • 2016
  • In: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 43:12, s. 5909-5917
  • Journal article (peer-reviewed)abstract
    • We show observations from the Magnetospheric Multiscale (MMS) mission of whistler mode waves in the Earth's low-latitude boundary layer (LLBL) during a magnetic reconnection event. The waves propagated obliquely to the magnetic field toward the X line and were confined to the edge of a southward jet in the LLBL. Bipolar parallel electric fields interpreted as electrostatic solitary waves (ESW) are observed intermittently and appear to be in phase with the parallel component of the whistler oscillations. The polarity of the ESWs suggests that if they propagate with the waves, they are electron enhancements as opposed to electron holes. The reduced electron distribution shows a shoulder in the distribution for parallel velocities between 17,000 and 22,000 km/s, which persisted during the interval when ESWs were observed, and is near the phase velocity of the whistlers. This shoulder can drive Langmuir waves, which were observed in the high-frequency parallel electric field data.
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18.
  • Alekeyenko, Artyom A., et al. (author)
  • Sequence-Specific Targeting of Dosage Compensation in Drosophila Favors an Active Chromatin Context
  • 2012
  • In: PLoS Genetics. - San Francisco : Public Library of Science. - 1553-7390 .- 1553-7404. ; 8:4, s. e1002646-
  • Journal article (peer-reviewed)abstract
    • The Drosophila MSL complex mediates dosage compensation by increasing transcription of the single X chromosome in males approximately two-fold. This is accomplished through recognition of the X chromosome and subsequent acetylation of histone H4K16 on X-linked genes. Initial binding to the X is thought to occur at "entry sites" that contain a consensus sequence motif ("MSL recognition element" or MRE). However, this motif is only similar to 2 fold enriched on X, and only a fraction of the motifs on X are initially targeted. Here we ask whether chromatin context could distinguish between utilized and non-utilized copies of the motif, by comparing their relative enrichment for histone modifications and chromosomal proteins mapped in the modENCODE project. Through a comparative analysis of the chromatin features in male S2 cells (which contain MSL complex) and female Kc cells (which lack the complex), we find that the presence of active chromatin modifications, together with an elevated local GC content in the surrounding sequences, has strong predictive value for functional MSL entry sites, independent of MSL binding. We tested these sites for function in Kc cells by RNAi knockdown of Sxl, resulting in induction of MSL complex. We show that ectopic MSL expression in Kc cells leads to H4K16 acetylation around these sites and a relative increase in X chromosome transcription. Collectively, our results support a model in which a pre-existing active chromatin environment, coincident with H3K36me3, contributes to MSL entry site selection. The consequences of MSL targeting of the male X chromosome include increase in nucleosome lability, enrichment for H4K16 acetylation and JIL-1 kinase, and depletion of linker histone H1 on active X-linked genes. Our analysis can serve as a model for identifying chromatin and local sequence features that may contribute to selection of functional protein binding sites in the genome.
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19.
  • Barrasa, Juan I., et al. (author)
  • DNA elements tether canonical Polycomb Repressive Complex 1 to human genes
  • 2023
  • In: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 51:21, s. 11613-11633
  • Journal article (peer-reviewed)abstract
    • Development of multicellular animals requires epigenetic repression by Polycomb group proteins. The latter assemble in multi-subunit complexes, of which two kinds, Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2), act together to repress key developmental genes. How PRC1 and PRC2 recognize specific genes remains an open question. Here we report the identification of several hundreds of DNA elements that tether canonical PRC1 to human developmental genes. We use the term tether to describe a process leading to a prominent presence of canonical PRC1 at certain genomic sites, although the complex is unlikely to interact with DNA directly. Detailed analysis indicates that sequence features associated with PRC1 tethering differ from those that favour PRC2 binding. Throughout the genome, the two kinds of sequence features mix in different proportions to yield a gamut of DNA elements that range from those tethering predominantly PRC1 or PRC2 to ones capable of tethering both complexes. The emerging picture is similar to the paradigmatic targeting of Polycomb complexes by Polycomb Response Elements (PREs) of Drosophila but providing for greater plasticity. [GRAPHICS]
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20.
  • Berkaeva, Maria, et al. (author)
  • Functional analysis of Drosophila polytene chromosomes decompacted unit: the interband
  • 2009
  • In: Chromosome Research. - : Springer Science and Business Media LLC. - 0967-3849 .- 1573-6849. ; 17:6, s. 745-754
  • Journal article (peer-reviewed)abstract
    • Differential compaction of the interphase chromosomes is important for proper functioning of the eukaryotic genome. Such non-uniform compaction is most easily observed in Drosophila salivary gland polytene chromosomes as a reproducible banding pattern. Functional mechanisms underlying the establishment and maintenance of the banding pattern remain unclear but have been hypothesized to involve transcription and chromatin insulators. We tested functional properties of DNA fragments from several transcriptionally inert interband regions that behave as autonomous decompacted units of polytene chromosomes. Our results suggest that, in the absence of transcription, the decondensed state of interband regions does not depend on the presence of insulator elements but instead correlates with the presence of transcriptional enhancers.
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21.
  • Cameron, Sarina R., et al. (author)
  • PTE, a novel module to target Polycomb Repressive Complex 1 to the human cyclin D2 (CCND2) oncogene
  • 2018
  • In: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 293:37, s. 14342-14358
  • Journal article (peer-reviewed)abstract
    • Polycomb group proteins are essential epigenetic repressors. They form multiple protein complexes of which two kinds, PRC1 and PRC2, are indispensable for repression. Although much is known about their biochemical properties, how mammalian PRC1 and PRC2 are targeted to specific genes is poorly understood. Here, we establish the cyclin D2 (CCND2) oncogene as a simple model to address this question. We provide the evidence that the targeting of PRC1 to CCND2 involves a dedicated PRC1-targeting element (PTE). The PTE appears to act in concert with an adjacent cytosine-phosphate-guanine (CpG) island to arrange for the robust binding of PRC1 and PRC2 to repressed CCND2. Our findings pave the way to identify sequence-specific DNA-binding proteins implicated in the targeting of mammalian PRC1 complexes and provide novel link between polycomb repression and cancer.
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22.
  • Dellino, Gaetano I, et al. (author)
  • Polycomb silencing blocks transcription initiation.
  • 2004
  • In: Molecular Cell. - 1097-2765 .- 1097-4164. ; 13:6, s. 887-93
  • Journal article (peer-reviewed)abstract
    • Polycomb (PcG) complexes maintain the silent state of target genes. The mechanism of silencing is not known but has been inferred to involve chromatin packaging to block the access of transcription factors. We have studied the effect of PcG silencing on the hsp26 heat shock promoter. While silencing does decrease the accessibility of some restriction enzyme sites to some extent, it does not prevent the binding of TBP, RNA polymerase, or the heat shock factor to the hsp26 promoter, as shown by chromatin immunoprecipitation. However, we find that in the repressed state, the RNA polymerase cannot initiate transcription. We conclude that, rather than altering chromatin structure to block accessibility, PcG silencing in this construct targets directly the activity of the transcriptional machinery at the promoter.
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23.
  • Demakov, Sergei, et al. (author)
  • Molecular and genetic organization of Drosophila melanogaster polytene chromosomes : evidence for two types of interband regions
  • 2004
  • In: Genetica. - 0016-6707 .- 1573-6857. ; 122:3, s. 311-324
  • Journal article (peer-reviewed)abstract
    • The 3A and 60E regions of Drosophila melanogaster polytene chromosomes containing inserted copies of the P[1ArB] transposon have been subjected to an electron microscopic (EM) analysis. We show that both inserts led to formation of new bands within the interband regions 3A4/A6 and 60E8-9/E10. This allowed us to clone DNA of these interbands. Their sequences, as well as those of DNA from other four interbands described earlier, have been analyzed. We have found that, with the exception of 60E8-9/E10 interband, all other five regions under study corresponded to 5' or 3' ends of genes. We have further obtained the evidence for 60E8-9/E10 interband to harbor the 'housekeeping' RpL19 gene, which is transcribed in many tissues, including salivary glands. Based upon the genetic heterogeneity of the interbands observed a revised model of polytene chromosome organization is discussed.
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24.
  • Dorafshan, Eshagh, et al. (author)
  • Ash1 counteracts Polycomb repression independent of histone H3 lysine 36 methylation
  • 2019
  • In: EMBO Reports. - : WILEY. - 1469-221X .- 1469-3178. ; 20:4
  • Journal article (peer-reviewed)abstract
    • Polycomb repression is critical for metazoan development. Equally important but less studied is the Trithorax system, which safeguards Polycomb target genes from the repression in cells where they have to remain active. It was proposed that the Trithorax system acts via methylation of histone H3 at lysine 4 and lysine 36 (H3K36), thereby inhibiting histone methyltransferase activity of the Polycomb complexes. Here we test this hypothesis by asking whether the Trithorax group protein Ash1 requires H3K36 methylation to counteract Polycomb repression. We show that Ash1 is the only Drosophila H3K36-specific methyltransferase necessary to prevent excessive Polycomb repression of homeotic genes. Unexpectedly, our experiments reveal no correlation between the extent of H3K36 methylation and the resistance to Polycomb repression. Furthermore, we find that complete substitution of the zygotic histone H3 with a variant in which lysine 36 is replaced by arginine does not cause excessive repression of homeotic genes. Our results suggest that the model, where the Trithorax group proteins methylate histone H3 to inhibit the histone methyltransferase activity of the Polycomb complexes, needs revision.
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25.
  • Dorafshan, Eshagh, et al. (author)
  • Does Ash1 counteract Polycomb repression by methylating H3K36?
  • Other publication (other academic/artistic)abstract
    • Polycomb repression is critical to maintain cell type specific genome expression programs in a wide range of multicellular animals. Equally important but less studied is the Trithorax group system, which safeguards Polycomb target genes from the repression in cells where they have to remain active. Based on in vitro studies it was proposed that the Trithorax group system acts via methylation of histone H3 at Lysine 4 (H3K4) and Lysine 36 (H3K36) thereby inhibiting histone methyltransferase activity of the Polycomb complexes. This hypothesis is yet to be comprehensively tested in vivo. Here we used the power of the Drosophila model to investigate how the Trithorax group protein Ash1 and the H3K36 methylation counteract Polycomb repression. We show, for the first time, that Ash1 is the only Drosophila H3K36-specific methyltransferase required to prevent excessive Polycomb repression of homeotic genes. Unexpectedly, our experiments revealed no correlation between the extent of H3K36 methylation and the resistance to Polycomb repression. Furthermore, we find that complete substitution of the zygotic histone H3 with a variant in which Lysine 36 is replaced by Arginine does not cause excessive repression of Drosophila homeotic genes. Together with earlier studies, our results suggest that the model, where the Trithorax group proteins methylate histone H3 to inhibit the histone methyltransferase activity of the Polycomb complexes, may need to be reevaluated.
  •  
26.
  •  
27.
  • Dorafshan, Eshagh, et al. (author)
  • Genetic Dissection Reveals the Role of Ash1 Domains in Counteracting Polycomb Repression
  • 2019
  • In: G3. - : The Genetics Society of America. - 2160-1836. ; 9:11, s. 3801-3812
  • Journal article (peer-reviewed)abstract
    • Antagonistic functions of Polycomb and Trithorax proteins are essential for proper development of all metazoans. While the Polycomb proteins maintain the repressed state of many key developmental genes, the Trithorax proteins ensure that these genes stay active in cells where they have to be expressed. Ash1 is the Trithorax protein that was proposed to counteract Polycomb repression by methylating lysine 36 of histone H3. However, it was recently shown that genetic replacement of Drosophila histone H3 with the variant that carried Arginine instead of Lysine at position 36 did not impair the ability of Ash1 to counteract Polycomb repression. This argues that Ash1 counteracts Polycomb repression by methylating yet unknown substrate(s) and that it is time to look beyond Ash1 methyltransferase SET domain, at other evolutionary conserved parts of the protein that received little attention. Here we used Drosophila genetics to demonstrate that Ash1 requires each of the BAH, PHD and SET domains to counteract Polycomb repression, while AT hooks are dispensable. Our findings argue that, in vivo, Ash1 acts as a multimer. Thereby it can combine the input of the SET domain and PHD-BAH cassette residing in different peptides. Finally, using new loss of function alleles, we show that zygotic Ash1 is required to prevent erroneous repression of homeotic genes of the bithorax complex in the embryo.
  •  
28.
  • Dorafshan, Eshagh, et al. (author)
  • Hierarchical recruitment of Polycomb complexes revisited
  • 2017
  • In: Nucleus. - : Taylor & Francis Group. - 1949-1034 .- 1949-1042. ; 8:5, s. 496-505
  • Journal article (peer-reviewed)abstract
    • Polycomb Group (PcG) proteins epigenetically repress key developmental genes and thereby control alternative cell fates. PcG proteins act as complexes that can modify histones and these histone modifications play a role in transmitting the memory of the repressed state as cells divide. Here we consider mainstream models that link histone modifications to hierarchical recruitment of PcG complexes and compare them to results of a direct test of interdependence between PcG complexes for recruitment to Drosophila genes. The direct test indicates that PcG complexes do not rely on histone modifications to recognize their target genes but use them to stabilize the interactions within large chromatin domains. It also shows that multiple strategies are used to coordinate the targeting of PcG complexes to different genes, which may make the repression of these genes more or less robust.
  •  
29.
  • Dorafshan Esfahani, Eshagh, 1980- (author)
  • Methyltransferase Ash1, histone methylation and their impact on Polycomb repression
  • 2018
  • Doctoral thesis (other academic/artistic)abstract
    • Antagonistic interactions between Polycomb Group (PcG) and Trithorax Group (TrxG) proteins orchestrate the expression of key developmental genes. Distinct maternally loaded repressors establish the silenced state of these genes in cells where they should not be expressed and later PcG proteins sense whether a target gene is inactive and maintain the repression throughout multiple cell divisions. PcG proteins are targeted to genes by DNA elements called Polycomb Response Elements (PREs). The proteins form two major classes of complexes, namely Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2). Mechanistic details of Polycomb repression are not fully understood, however, tri-methylation of Lysine 27 of histone H3 (H3K27me3) is essential for this process. Using Drosophila cell lines deficient for either PRC1 or PRC2, I investigated the role of H3K27 methylation and the interdependence of PRC1 complexes for their recruitment to PREs. My results indicate that recruitment of PcG complexes to PREs proceed via multiple pathways and that H3K27 methylation is not needed for their targeting. However, the methylation is required to stabilize interactions of PRE-anchored PcG complexes with surrounding chromatin.TrxG proteins prevent erroneous repression of Polycomb target genes where these genes need to be expressed. Ash1 is a TrxG protein which binds Polycomb target genes when they are transcriptionally active. It contains a SET domain which methylates Lysine 36 of histone H3 (H3K36). In vitro, histone H3 methylated at K36 is a poor substrate for H3K27 methylation by PRC2. This prompted a model where Ash1 counteracts Polycomb repression through H3K36 methylation. However, this model was never tested in vivo and does not consider several experimental observations. First, in the ash1 mutant flies the bulk H3K36me2/H3K36me3 levels remain unchanged. Second, in Drosophila, there are two other H3K36-specific histone methyltransferases, NSD and Set2, which should be capable to inhibit PRC2. Third, Ash1 contains multiple evolutionary conserved domains whose roles have not been investigated. Therefore, I asked whether H3K36 methylation is critical for Ash1 to counteract Polycomb repression in vivo and whether NSD and Set2 proteins contribute to this process. I used flies lacking endogenous histone genes and complemented them with transgenic histone genes where Lysine 36 is replaced by Arginine. In these animals, I assayed erroneous repression of HOX genes as a readout for erroneous Polycomb repression. I used the same readout in the NSD or Set2 mutant flies. I also asked if other conserved domains of Ash1 are essential for its function. In addition to SET and domain, Ash1 contains three AT hook motifs as well as BAH and PHD domains. I genetically complemented ash1 loss of function animals with transgenic Ash1 variants, in each, one domain of Ash1 is deleted. I found that Ash1 is the only H3K36-specific histone methyltransferase which counteracts Polycomb repression in Drosophila. My findings suggest that the model, where Ash1 counteracts PcG repression by inhibiting PRC2 via methylation of H3K36, has to be revised. I also showed that, in vivo, Ash1 acts as a multimer and requires SET, BAH and PHD domains to counteract Polycomb repression.This work led to two main conclusions. First, trimethylation of H3K27 is not essential for targeting PcG proteins to PREs but acts afterwards to stabilize their interaction with the chromatin of the neighboring genes. Second, while SET domain is essential for Ash1 to oppose Polycomb repression, methylation of H3K36 does not play a central role in the process.
  •  
30.
  • Egelhofer, Thea A, et al. (author)
  • An assessment of histone-modification antibody quality
  • 2011
  • In: Nature Structural & Molecular Biology. - : Springer Science and Business Media LLC. - 1545-9993 .- 1545-9985. ; 18:1, s. 91-93
  • Journal article (peer-reviewed)abstract
    • We have tested the specificity and utility of more than 200 antibodies raised against 57 different histone modifications in Drosophila melanogaster, Caenorhabditis elegans and human cells. Although most antibodies performed well, more than 25% failed specificity tests by dot blot or western blot. Among specific antibodies, more than 20% failed in chromatin immunoprecipitation experiments. We advise rigorous testing of histone-modification antibodies before use, and we provide a website for posting new test results (http://compbio.med.harvard.edu/antibodies/).
  •  
31.
  • Furberg, Helena, et al. (author)
  • Genome-wide meta-analyses identify multiple loci associated with smoking behavior
  • 2010
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 134-441
  • Journal article (peer-reviewed)abstract
    • Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
  •  
32.
  • Gingell, Imogen, et al. (author)
  • MMS Observations and Hybrid Simulations of Surface Ripples at a Marginally Quasi-Parallel Shock
  • 2017
  • In: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 122:11, s. 11003-11017
  • Journal article (peer-reviewed)abstract
    • Simulations and observations of collisionless shocks have shown that deviations of the nominal local shock normal orientation, that is, surface waves or ripples, are expected to propagate in the ramp and overshoot of quasi-perpendicular shocks. Here we identify signatures of a surface ripple propagating during a crossing of Earth's marginally quasi-parallel (theta(Bn) similar to 45 degrees) or quasi-parallel bow shock on 27 November 2015 06: 01: 44 UTC by the Magnetospheric Multiscale (MMS) mission and determine the ripple's properties using multispacecraft methods. Using two-dimensional hybrid simulations, we confirm that surface ripples are a feature of marginally quasi-parallel and quasi-parallel shocks under the observed solar wind conditions. In addition, since these marginally quasi-parallel and quasi-parallel shocks are expected to undergo a cyclic reformation of the shock front, we discuss the impact of multiple sources of nonstationarity on shock structure. Importantly, ripples are shown to be transient phenomena, developing faster than an ion gyroperiod and only during the period of the reformation cycle when a newly developed shock ramp is unaffected by turbulence in the foot. We conclude that the change in properties of the ripple observed by MMS is consistent with the reformation of the shock front over a time scale of an ion gyroperiod.
  •  
33.
  • Goodrich, Katherine A., et al. (author)
  • MMS Observations of Electrostatic Waves in an Oblique Shock Crossing
  • 2018
  • In: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 123:11, s. 9430-9442
  • Journal article (peer-reviewed)abstract
    • High-resolution particle and wave measurements taken during an oblique bow shock crossing by the Magnetospheric Multiscale (MMS) mission are analyzed. Two regions of differing magnetic behavior are identified within the shock, one with active magnetic fluctuations and one with laminar interplanetary magnetic field topology. A prominent reflected ion population is observed in both regions. The active magnetic region is characterized by large-amplitude (>100 mV/m) electrostatic solitary waves, electron Bernstein waves, and ion acoustic waves, along with intermittent current activity and localized electron heating. In the region of laminar magnetic field, ion acoustic waves are prominently observed. Solar wind ion deceleration is observed in both regions of active and laminar magnetic field. All observations suggest that solar wind deceleration can occur as a result of multiple independent processes, in this case current and ion-ion instabilities.
  •  
34.
  • Groza, Paula Petronela, 1991- (author)
  • RNA-mediated gene expression regulation
  • 2024
  • Doctoral thesis (other academic/artistic)abstract
    • The regulation of gene expression is a key mechanism that underlies all biological processes, from embryonic development to the onset and progression of various diseases, including cancer. A growing body of evidence places RNA molecules at the center of critical regulatory steps in gene expression. They serve not only as intermediate molecules between DNA and proteins but also act as regulators of processes such as alternative splicing (AS) and translation, among others. This thesis focuses on the role of RNA in gene expression regulation. Specifically, it addresses how intrinsic properties of RNA, RNA chemical modifications, and RNA binding proteins (RBPs) can control gene expression regulatory processes.The first part tackles specific aspects of AS in neurodifferentiation. Paper I shows how RBPs affect AS in mouse embryonic stem cells (ESCs). Within this work, we identified ZFP207, a known transcription factor (TF), as an RBP with a crucial role in modulating the AS of key transcripts for neurodifferentiation. Depletion of ZFP207 in mouse ESCs led to abnormal AS patterns and a differentiated cell phenotype.The second part (Papers II-IV) focuses on the role of RNA modifications in disease. In Paper II, the publicly available literature linking deregulations of RNA modifications and their regulatory proteins with different diseases was curated. The obtained information was integrated into the 2021 update of the MODOMICS database, the most extensive RNA modifications database to date. Papers III and IV exemplify how two different RNA marks contribute to breast cancer. Paper III shows how METTL3, the enzyme responsible for N6-methyladenosine (m6A) deposition on messenger RNA (mRNA), affects tumorigenesis by modulating AS. METTL3-mediated AS regulation can be done either by depositing m6A at the intron-exon junctions of specific transcripts or on transcripts encoding for splicing and transcription factors, such as MYC. Changes in RNA modifications of ribosomal RNA (rRNA) affect stability, folding, and interactions with other molecules, leading to perturbed translation efficiency (TE). In Paper IV, we focused on the role of 2'-O-methylation, the most abundant rRNA modification, and its catalytic enzyme, fibrillarin (FBL), in triple-negative breast cancer (TNBC). We discovered that certain proto-oncogenes associated with breast cancer displayed a reduction in TE upon FBL depletion. Additionally, we identified 7 2'-O-methylation sites that might mediate TE regulation in a TNBC cellular model. Moreover, our study uncovered alterations in the ribosomal protein composition within the ribosomes of FBL-depleted cells. Our results support the pivotal role of 2'-O-methylation in controlling the translational capabilities of ribosomes in TNBC cells.Overall, this work encompasses multiple aspects of gene expression regulation and describes how RNA modifications and RBPs modulate the fate of specific transcripts by controlling AS or translation.
  •  
35.
  • Hasegawa, H., et al. (author)
  • Kelvin-Helmholtz waves at the Earth's magnetopause : Multiscale development and associated reconnection
  • 2009
  • In: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 114:12, s. A12207-
  • Journal article (peer-reviewed)abstract
    • We examine traversals on 20 November 2001 of the equatorial magnetopause boundary layer simultaneously at similar to 1500 magnetic local time (MLT) by the Geotail spacecraft and at similar to 1900 MLT by the Cluster spacecraft, which detected rolled-up MHD-scale vortices generated by the Kelvin-Helmholtz instability (KHI) under prolonged northward interplanetary magnetic field conditions. Our purpose is to address the excitation process of the KHI, MHD-scale and ion-scale structures of the vortices, and the formation mechanism of the low-latitude boundary layer (LLBL). The observed KH wavelength (>4 x 10(4) km) is considerably longer than predicted by the linear theory from the thickness (similar to 1000 km) of the dayside velocity shear layer. Our analyses suggest that the KHI excitation is facilitated by combined effects of the formation of the LLBL presumably through high-latitude magnetopause reconnection and compressional magnetosheath fluctuations on the dayside, and that breakup and/or coalescence of the vortices are beginning around 1900 MLT. Current layers of thickness a few times ion inertia length similar to 100 km and of magnetic shear similar to 60 degrees existed at the trailing edges of the vortices. Identified in one such current sheet were signatures of local reconnection: Alfvenic outflow jet within a bifurcated current sheet, nonzero magnetic field component normal to the sheet, and field-aligned beam of accelerated electrons. Because of its incipient nature, however, this reconnection process is unlikely to lead to the observed dusk-flank LLBL. It is thus inferred that the flank LLBL resulted from other mechanisms, namely, diffusion and/or remote reconnection unidentified by Cluster.
  •  
36.
  • Johlander, Andreas, 1990-, et al. (author)
  • Ion Acceleration Efficiency at the Earth's Bow Shock : Observations and Simulation Results
  • 2021
  • In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 914:2
  • Journal article (peer-reviewed)abstract
    • Collisionless shocks are some of the most efficient particle accelerators in heliospheric and astrophysical plasmas. Here we study and quantify ion acceleration at Earth's bow shock with observations from NASA's Magnetospheric Multiscale (MMS) satellites and in a global hybrid-Vlasov simulation. From the MMS observations, we find that quasiparallel shocks are more efficient at accelerating ions. There, up to 15% of the available energy goes into accelerating ions above 10 times their initial energy. Above a shock-normal angle of similar to 50 degrees, essentially no energetic ions are observed downstream of the shock. We find that ion acceleration efficiency is significantly lower when the shock has a low Mach number (M ( A ) < 6) while there is little Mach number dependence for higher values. We also find that ion acceleration is lower on the flanks of the bow shock than at the subsolar point regardless of the Mach number. The observations show that a higher connection time of an upstream field line leads to somewhat higher acceleration efficiency. To complement the observations, we perform a global hybrid-Vlasov simulation with realistic solar-wind parameters with the shape and size of the bow shock. We find that the ion acceleration efficiency in the simulation shows good quantitative agreement with the MMS observations. With the combined approach of direct spacecraft observations, we quantify ion acceleration in a wide range of shock angles and Mach numbers.
  •  
37.
  • Johlander, Andreas, 1990-, et al. (author)
  • Shock ripples observed by the MMS spacecraft : ion reflection and dispersive properties
  • 2018
  • In: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 0741-3335 .- 1361-6587. ; 60
  • Journal article (peer-reviewed)abstract
    • Shock ripples are ion-inertial-scale waves propagating within the front region of magnetized quasi-perpendicular collisionless shocks. The ripples are thought to influence particle dynamics and acceleration at shocks. With the four magnetospheric multiscale (MMS) spacecraft, it is for the first time possible to fully resolve the small scale ripples in space. We use observations of one slow crossing of the Earth's non-stationary bow shock by MMS. From multi-spacecraft measurements we show that the non-stationarity is due to ripples propagating along the shock surface. We find that the ripples are near linearly polarized waves propagating in the coplanarity plane with a phase speed equal to the local Alfvén speed and have a wavelength close to 5 times the upstream ion inertial length. The dispersive properties of the ripples resemble those of Alfvén ion cyclotron waves in linear theory. Taking advantage of the slow crossing by the four MMS spacecraft, we map the shock-reflected ions as a function of ripple phase and distance from the shock. We find that ions are preferentially reflected in regions of the wave with magnetic field stronger than the average overshoot field, while in the regions of lower magnetic field, ions penetrate the shock to the downstream region.
  •  
38.
  • Kahn, Tatyana G., et al. (author)
  • Combinatorial Interactions Are Required for the Efficient Recruitment of Pho Repressive Complex (PhoRC) to Polycomb Response Elements
  • 2014
  • In: PLOS Genetics. - : PLOS. - 1553-7390 .- 1553-7404. ; 10:7, s. e1004495-
  • Journal article (peer-reviewed)abstract
    • Polycomb Group (PcG) proteins are epigenetic repressors that control metazoan development and cell differentiation. In Drosophila, PcG proteins form five distinct complexes targeted to genes by Polycomb Response Elements (PREs). Of all PcG complexes PhoRC is the only one that contains a sequence-specific DNA binding subunit (PHO or PHOL), which led to a model that places PhoRC at the base of the recruitment hierarchy. Here we demonstrate that in vivo PHO is preferred to PHOL as a subunit of PhoRC and that PHO and PHOL associate with PREs and a subset of transcriptionally active promoters. Although the binding to the promoter sites depends on the quality of recognition sequences, the binding to PREs does not. Instead, the efficient recruitment of PhoRC to PREs requires the SFMBT subunit and crosstalk with Polycomb Repressive Complex 1. We find that human YY1 protein, the ortholog of PHO, binds sites at active promoters in the human genome but does not bind most PcG target genes, presumably because the interactions involved in the targeting to Drosophila PREs are lost in the mammalian lineage. We conclude that the recruitment of PhoRC to PREs is based on combinatorial interactions and propose that such a recruitment strategy is important to attenuate the binding of PcG proteins when the target genes are transcriptionally active. Our findings allow the appropriate placement of PhoRC in the PcG recruitment hierarchy and provide a rationale to explain why YY1 is unlikely to serve as a general recruiter of mammalian Polycomb complexes despite its reported ability to participate in PcG repression in flies.
  •  
39.
  • Kahn, Tatyana G., et al. (author)
  • Interdependence of PRC1 and PRC2 for recruitment to Polycomb Response Elements
  • 2016
  • In: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 44:21, s. 10132-10149
  • Journal article (peer-reviewed)abstract
    • Polycomb Group (PcG) proteins are epigenetic repressors essential for control of development and cell differentiation. They form multiple complexes of which PRC1 and PRC2 are evolutionary conserved and obligatory for repression. The targeting of PRC1 and PRC2 is poorly understood and was proposed to be hierarchical and involve tri-methylation of histone H3 (H3K27me3) and/or monoubiquitylation of histone H2A (H2AK118ub). Here, we present a strict test of this hypothesis using the Drosophila model. We discover that neither H3K27me3 nor H2AK118ub is required for targeting PRC complexes to Polycomb Response Elements (PREs). We find that PRC1 can bind PREs in the absence of PRC2 but at many PREs PRC2 requires PRC1 to be targeted. We show that one role of H3K27me3 is to allow PcG complexes anchored at PREs to interact with surrounding chromatin. In contrast, the bulk of H2AK118ub is unrelated to PcG repression. These findings radically change our view of how PcG repression is targeted and suggest that PRC1 and PRC2 can communicate independently of histone modifications.
  •  
40.
  • Kahn, Tatyana G, et al. (author)
  • Polycomb complexes and the propagation of the methylation mark at the Drosophila ubx gene
  • 2006
  • In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 281:39, s. 29064-29075
  • Journal article (peer-reviewed)abstract
    • Polycomb group proteins are transcriptional repressors that control many developmental genes. The Polycomb group protein Enhancer of Zeste has been shown in vitro to methylate specifically lysine 27 and lysine 9 of histone H3 but the role of this modification in Polycomb silencing is unknown. We show that H3 trimethylated at lysine 27 is found on the entire Ubx gene silenced by Polycomb. However, Enhancer of Zeste and other Polycomb group proteins stay primarily localized at their response elements, which appear to be the least methylated parts of the silenced gene. Our results suggest that, contrary to the prevailing view, the Polycomb group proteins and methyltransferase complexes are recruited to the Polycomb response elements independently of histone methylation and then loop over to scan the entire region, methylating all accessible nucleosomes. We propose that the Polycomb chromodomain is required for the looping mechanism that spreads methylation over a broad domain, which in turn is required for the stability of the Polycomb group protein complex. Both the spread of methylation from the Polycomb response elements, and the silencing effect can be blocked by the gypsy insulator.
  •  
41.
  • Kahn, Tatyana G., et al. (author)
  • Topological screen identifies hundreds of Cp190- and CTCF-dependent Drosophila chromatin insulator elements
  • 2023
  • In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 9:5
  • Journal article (peer-reviewed)abstract
    • Drosophila insulators were the first DNA elements found to regulate gene expression by delimiting chromatin contacts. We still do not know how many of them exist and what impact they have on the Drosophila genome folding. Contrary to vertebrates, there is no evidence that fly insulators block cohesin-mediated chromatin loop extrusion. Therefore, their mechanism of action remains uncertain. To bridge these gaps, we mapped chromatin contacts in Drosophila cells lacking the key insulator proteins CTCF and Cp190. With this approach, we found hundreds of insulator elements. Their study indicates that Drosophila insulators play a minor role in the overall genome folding but affect chromatin contacts locally at many loci. Our observations argue that Cp190 promotes cobinding of other insulator proteins and that the model, where Drosophila insulators block chromatin contacts by forming loops, needs revision. Our insulator catalog provides an important resource to study mechanisms of genome folding.
  •  
42.
  • Kharchenko, Peter V, et al. (author)
  • Comprehensive analysis of the chromatin landscape in Drosophila melanogaster
  • 2011
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 471:7339, s. 480-485
  • Journal article (peer-reviewed)abstract
    • Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.
  •  
43.
  • Lee, Hun-Goo, et al. (author)
  • Genome-wide activities of Polycomb complexes control pervasive transcription
  • 2015
  • In: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 25:8, s. 1170-1181
  • Journal article (peer-reviewed)abstract
    • Polycomb group (PcG) complexes PRC1 and PRC2 are well known for silencing specific developmental genes. PRC2 is a methyltransferase targeting histone H3K27 and producing H3K27me3, essential for stable silencing. Less well known but quantitatively much more important is the genome-wide role of PRC2 that dimethylates similar to 70% of total H3K27. We show that H3K27me2 occurs in inverse proportion to transcriptional activity in most non-PcG target genes and intergenic regions and is governed by opposing roaming activities of PRC2 and complexes containing the H3K27 demethylase UTX. Surprisingly, loss of H3K27me2 results in global transcriptional derepression proportionally greatest in silent or weakly transcribed intergenic and genic regions and accompanied by an increase of H3K27ac and H3K4me1. H3K27me2 therefore sets a threshold that prevents random, unscheduled transcription all over the genome and even limits the activity of highly transcribed genes. PRC1-type complexes also have global roles. Unexpectedly, we find a pervasive distribution of histone H2A ubiquitylated at lysine 118 (H2AK118ub) outside of canonical PcG target regions, dependent on the RING/Sce subunit of PRC1-type complexes. We show, however, that H2AK118ub does not mediate the global PRC2 activity or the global repression and is predominantly produced by a new complex involving L(3) 73Ah, a homolog of mammalian PCGF3.
  •  
44.
  • Lindehell, Henrik, 1984-, et al. (author)
  • Methylation of lysine 36 on histone H3 is required to control transposon activities in somatic cells
  • 2023
  • In: Life Science Alliance. - : NLM (Medline). - 2575-1077. ; 6:8
  • Journal article (peer-reviewed)abstract
    • Transposable elements constitute a substantial portion of most eukaryotic genomes and their activity can lead to developmental and neuronal defects. In the germline, transposon activity is antagonized by the PIWI-interacting RNA pathway tasked with repression of transposon transcription and degrading transcripts that have already been produced. However, most of the genes required for transposon control are not expressed outside the germline, prompting the question: what causes deleterious transposons activity in the soma and how is it managed? Here, we show that disruptions of the Histone 3 lysine 36 methylation machinery led to increased transposon transcription in Drosophila melanogaster brains and that there is division of labour for the repression of transposable elements between the different methyltransferases Set2, NSD, and Ash1. Furthermore, we show that disruption of methylation leads to somatic activation of key genes in the PIWI-interacting RNA pathway and the preferential production of RNA from dual-strand piRNA clusters.
  •  
45.
  • Lindehell, Henrik, 1984-, et al. (author)
  • The role of H3K36 methylation and associated methyltransferases in chromosome-specific gene regulation
  • 2021
  • In: Science Advances. - : American Association for the Advancement of Science. - 2375-2548. ; 7:40
  • Journal article (peer-reviewed)abstract
    • In Drosophila, two chromosomes require special mechanisms to balance their transcriptional output to the rest of the genome. These are the male-specific lethal complex targeting the male X chromosome and Painting of fourth targeting chromosome 4. Here, we explore the role of histone H3 methylated at lysine-36 (H3K36) and the associated methyltransferases—Set2, NSD, and Ash1—in these two chromosome-specific systems. We show that the loss of Set2 impairs the MSL complex–mediated dosage compensation; however, the effect is not recapitulated by H3K36 replacement and indicates an alternative target of Set2. Unexpectedly, balanced transcriptional output from the fourth chromosome requires intact H3K36 and depends on the additive functions of NSD and Ash1. We conclude that H3K36 methylation and the associated methyltransferases are important factors to balance transcriptional output of the male X chromosome and the fourth chromosome. Furthermore, our study highlights the pleiotropic effects of these enzymes.
  •  
46.
  • Lizana, Ludvig, 1977-, et al. (author)
  • Polycomb proteins translate histone methylation to chromatin folding
  • 2023
  • In: Journal of Biological Chemistry. - : Elsevier. - 0021-9258 .- 1083-351X. ; 299:9
  • Journal article (peer-reviewed)abstract
    • Epigenetic repression often involves covalent histone modifications. Yet, how the presence of a histone mark translates into changes in chromatin structure that ultimately benefits the repression is largely unclear. Polycomb group proteins comprise a family of evolutionarily conserved epigenetic repressors. They act as multi-subunit complexes one of which tri-methylates histone H3 at Lysine 27 (H3K27). Here we describe a novel Monte Carlo–Molecular Dynamics simulation framework, which we employed to discover that stochastic interaction of Polycomb Repressive Complex 1 (PRC1) with tri-methylated H3K27 is sufficient to fold the methylated chromatin. Unexpectedly, such chromatin folding leads to spatial clustering of the DNA elements bound by PRC1. Our results provide further insight into mechanisms of epigenetic repression and the process of chromatin folding in response to histone methylation.
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47.
  • Lizana, Ludvig, 1977-, et al. (author)
  • The scales, mechanisms, and dynamics of the genome architecture
  • 2024
  • In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 10:15
  • Research review (peer-reviewed)abstract
    • Even when split into several chromosomes, DNA molecules that make up our genome are too long to fit into the cell nuclei unless massively folded. Such folding must accommodate the need for timely access to selected parts of the genome by transcription factors, RNA polymerases, and DNA replication machinery. Here, we review our current understanding of the genome folding inside the interphase nuclei. We consider the resulting genome architecture at three scales with a particular focus on the intermediate (meso) scale and summarize the insights gained from recent experimental observations and diverse computational models.
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48.
  •  
49.
  • Lundkvist, Moa J., et al. (author)
  • Forecasting histone methylation by Polycomb complexes with minute-scale precision
  • 2023
  • In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 9:51
  • Journal article (peer-reviewed)abstract
    • Animals use the Polycomb system to epigenetically repress developmental genes. The repression requires trimethylation of lysine 27 of histone H3 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2), but the dynamics of this process is poorly understood. To bridge the gap, we developed a computational model that forecasts H3K27 methylation in Drosophila with high temporal resolution and spatial accuracy of contemporary experimental techniques. Using this model, we show that pools of methylated H3K27 in dividing cells are defined by the effective concentration of PRC2 and the replication frequency. We find that the allosteric stimulation by preexisting H3K27me3 makes PRC2 better in methylating developmental genes as opposed to indiscriminate methylation throughout the genome. Applied to Drosophila development, our model argues that, in this organism, the intergenerationally inherited H3K27me3 does not “survive” rapid cycles of embryonic chromatin replication and is unlikely to transmit the memory of epigenetic repression to the offspring. Our model is adaptable to other organisms, including mice and humans.
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50.
  • Lundkvist, Moa J., 1992- (author)
  • Towards forecasting epigenetic repression
  • 2024
  • Doctoral thesis (other academic/artistic)abstract
    • Multicellular organisms form many different cell types from one genome, which requires differential gene activity. The Polycomb system upholds the correct gene expression programs by epigenetically silencing genes that encode critical transcription regulators. It is defined by the protein complexes Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). PRC2 methylates lysine 27 on histone H3 (H3K27) on nucleosomes. This is necessary for the repression, but it is not known why. In Drosophila melanogaster both PRC1 and PRC2 bind to DNA elements called PREs near the target genes. In human cells, PRC2 are tethered to CpG islands, but PRC1 tethering is not well understood. In paper I of the thesis we uncover the first comprehensive catalogue of DNA elements, Polycomb Tethering Elements (PTEs), that target PRC1 to human developmental genes. PTEs and CpG islands may be intermixed—forming a PRE equivalent—or offset from each other. Genes equipped with PTEs have low transcription and are stochastically reactivated upon deletion of their PTE. In paper II, we used a computational model to stochastically simulate both the random and targeted methylation by PRC2, to understand the dynamics of H3K27 methylation. The model was constrained by data, such as the levels of methylation in cells, allosteric stimulation of PRC2 by H3K27 trimethylation, and the differing catalytic efficiency of each successive methyl transfer to H3K27. We used it to investigate PRC2’s allosteric stimulation, the relationship between the rates of methylation and demethylation and cell cycle length, and how the rapid embryonic development of D. melanogaster affects the maternal contribution of H3K27me3 to the embryo. In paper III we used polymer modelling to investigate how chromatin folding by PRC1-H3K27me3 interactions affects contacts inside loci repressed by the Polycomb system. With these three studies, this thesis combines experimental and computational methods to further our understanding of epigenetic repression by the Polycomb system.
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