| 1. |
- Gingell, I., et al.
(författare)
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Statistics of Reconnecting Current Sheets in the Transition Region of Earth's Bow Shock
- 2020
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Ingår i: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 125:1
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Kang, Hyuckjoon, et al.
(författare)
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Variant Polycomb complexes in Drosophila consistent with ancient functional diversity
- 2022
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Ingår i: Science Advances. - : NLM (Medline). - 2375-2548. ; 8:36
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Barrasa, Juan I., et al.
(författare)
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DNA elements tether canonical Polycomb Repressive Complex 1 to human genes
- 2023
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 51:21, s. 11613-11633
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Groza, Paula Petronela, 1991-
(författare)
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RNA-mediated gene expression regulation
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 5. |
- Johlander, Andreas, 1990-, et al.
(författare)
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Ion Acceleration Efficiency at the Earth's Bow Shock : Observations and Simulation Results
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 914:2
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Tidskriftsartikel (refereegranskat)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.
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| 6. |
- Kahn, Tatyana G., et al.
(författare)
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Topological screen identifies hundreds of Cp190- and CTCF-dependent Drosophila chromatin insulator elements
- 2023
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 9:5
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Tidskriftsartikel (refereegranskat)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.
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| 7. |
- Lindehell, Henrik, 1984-, et al.
(författare)
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Methylation of lysine 36 on histone H3 is required to control transposon activities in somatic cells
- 2023
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Ingår i: Life Science Alliance. - : NLM (Medline). - 2575-1077. ; 6:8
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Tidskriftsartikel (refereegranskat)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.
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| 8. |
- Lindehell, Henrik, 1984-, et al.
(författare)
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The role of H3K36 methylation and associated methyltransferases in chromosome-specific gene regulation
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science. - 2375-2548. ; 7:40
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Tidskriftsartikel (refereegranskat)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.
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| 9. |
- Lizana, Ludvig, 1977-, et al.
(författare)
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Polycomb proteins translate histone methylation to chromatin folding
- 2023
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Ingår i: Journal of Biological Chemistry. - : Elsevier. - 0021-9258 .- 1083-351X. ; 299:9
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Tidskriftsartikel (refereegranskat)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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| 10. |
- Lizana, Ludvig, 1977-, et al.
(författare)
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The scales, mechanisms, and dynamics of the genome architecture
- 2024
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 10:15
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Forskningsöversikt (refereegranskat)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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