| 1. |
- He, Li, et al.
(författare)
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PRDM16 functions as a co-repressor in the BMP pathway to suppress neural stem cell proliferation
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BMP signalling acts as an instructive cue in multiple developmental processes such as tissue patterning, stem cell proliferation and differentiation. It remains unclear how the same signalling input can be translated into a diverse range of cell-specific outputs. Here we have identified PRDM16 as a key regulator for BMP-induced neural stem cell (NSC) quiescence. We have determined genomic distribution of the SMAD4/pSMAD complexes in quiescent and proliferating NSCs and find that PRDM16 tethers the SMAD4 and pSMAD1/5/8 proteins at their co-bound genomic sites to prevent transcriptional activation of cell proliferation genes. Loss of Prdm16 led to relocation of the SMAD complex to neighbouring genomic regions, leading to aberrant upregulation of BMP target genes. Such function of PRDM16 is also required for the specification of choroid plexus (ChP) epithelial cells. Using a single-cell resolution fluorescent in situapproach, we show that a SMAD/PRDM16 co-repressed gene, Wnt7b, and Wnt activity become upregulated in the Prdm16 mutant ChP, which correlates with abnormally elevated cell proliferation. Together, our work defines the mechanism by which SMAD4 and pSMAD1/5/8 repress gene expression during the induction of cell quiescence and suggests a regulatory circuit composed of BMP and Wnt signaling and PRDM16 in the control of stem cell behaviors.
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| 2. |
- He, Li, et al.
(författare)
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PRDM16 regulates a temporal transcriptional program to promote progression of cortical neural progenitors
- 2021
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 148:6
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Tidskriftsartikel (refereegranskat)abstract
- Radial glia (RG) in the neocortex sequentially generate distinct subtypes of projection neurons, accounting for the diversity and complex assembly of cortical neural circuits. Mechanismsthat drive the rapid and precise temporal progression of RG are beginning to be elucidated. Here, we reveal that the RG-specific transcriptional regulator PRDM16 promotes the transition of early to late phase of neurogenesis in the mouse neocortex. Loss of Prdm16 delays the timely progression of RG, leading to defective cortical laminar organization. Our genomic analyses demonstrate that PRDM16 regulates a subset of genes that are dynamically expressed between early and late neurogenesis. We show that PRDM16 suppresses target gene expression through limiting chromatin accessibility of permissive enhancers. We further confirm that crucial target genes regulated by PRDM16 are neuronal specification genes, cell cycle regulators and molecules required for neuronal migration. These findings provide evidence to support the finding that neural progenitors temporally shift the gene expression program to achieve neural cell diversity.
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| 3. |
- Lindblad-Toh, Kerstin, et al.
(författare)
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A high-resolution map of human evolutionary constraint using 29 mammals
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 478:7370, s. 476-482
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Tidskriftsartikel (refereegranskat)abstract
- The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering similar to 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for similar to 60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate-and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.
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| 4. |
- Regadas, Isabel, et al.
(författare)
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A unique histone 3 lysine 14 chromatin signature underlies tissue-specific gene regulation
- 2021
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 81:8, s. 1766-1780
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Tidskriftsartikel (refereegranskat)abstract
- Organismal development and cell differentiation critically depend on chromatin state transitions. However, certain developmentally regulated genes lack histone 3 lysine 9 and 27 acetylation (H3K9ac and H3K27ac, respectively) and histone 3 lysine 4 (H3K4) methylation, histone modifications common to most active genes. Here we describe a chromatin state featuring unique histone 3 lysine 14 acetylation (H3K14ac) peaks in key tissue-specific genes in Drosophila and human cells. Replacing H3K14 in Drosophila demonstrates that H3K14 is essential for expression of genes devoid of canonical histone modifications in the embryonic gut and larval wing imaginal disc, causing lethality and defective wing patterning. We find that the SWI/SNF protein Brahma (Brm) recognizes H3K14ac, that brm acts in the same genetic pathway as H3K14R, and that chromatin accessibility at H3K14ac-unique genes is decreased in H3K14R mutants. Our results show that acetylation of a single lysine is essential at genes devoid of canonical histone marks and uncover an important requirement for H3K14 in tissue-specific gene regulation.
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| 5. |
- Ueberschär, Malin, et al.
(författare)
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BEN-solo factors partition active chromatin to ensure proper gene activation in Drosophila
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The Drosophila genome encodes three BEN-solo proteins including Insensitive (Insv), Elba1 and Elba2 that possess activities in transcriptional repression and chromatin insulation. A fourth protein-Elba3-bridges Elba1 and Elba2 to form an ELBA complex. Here, we report comprehensive investigation of these proteins in Drosophila embryos. We assess common and distinct binding sites for Insv and ELBA and their genetic interdependencies. While Elba1 and Elba2 binding generally requires the ELBA complex, Elba3 can associate with chromatin independently of Elba1 and Elba2. We further demonstrate that ELBA collaborates with other insulators to regulate developmental patterning. Finally, we find that adjacent gene pairs separated by an ELBA bound sequence become less differentially expressed in ELBA mutants. Transgenic reporters confirm the insulating activity of ELBA- and Insv-bound sites. These findings define ELBA and Insv as general insulator proteins in Drosophila and demonstrate the functional importance of insulators to partition transcription units.
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| 6. |
- Ueberschär, Malin, 1991-, et al.
(författare)
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BEN-solo proteins regulate genome accessibility
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Active and silent transcriptional domains are established in parallel with the activation of the genome of a developing animal. Chromatin insulator elements separate transcription units and form barriers to limit the spread of different histone modifications. In contrast to other insulator binding proteins the BEN-solo proteins are expressed ubiquitously only at the stage of mid-blastula transition. They interact with other insulators and can partition the densely spaced transcription units in Drosophila ensuring their correct transcription, but their effect on chromatin architecture has never been explored. Here we show that the ELBA complex and Insv both regulate chromatin accessibility during genome activation. Many regions gain or lose signal in ATAC-seq in the mutants which is accompanied by changes in nascent transcription genome-wide. While ELBA contributes to the silencing of a reporter on the y chromosome, Insv appears to limit the spread of heterochromatin observed by the formation of HP1a-GFP foci. We conclude that ELBA and Insv act as chromatin barriers at a set of common target loci, but also diverge in their regulatory functions on heterochromatin, possibly via different interactors.
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| 7. |
- Ueberschär, Malin, 1991-, et al.
(författare)
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Insulator activity of paused promoters is independent of active transcription
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Insulators are a class of cis-regulatory elements that organize genome architecture and separate transcription units. Recent evidence suggests that highly transcribed genes co-localize with insulators at chromatin boundaries. However, whether active transcription contributes to chromatin insulation remains unclear. In this study we address whether highly transcribed promoters, which are also in a paused state in the Drosophila embryo, function as insulators with the ability to block enhancer-promoter interaction. Using a transgenic reporter assay, we show that some, but not all, paused promoters act as insulators. To further dissect functional contribution of promoter pausing to enhancer-blocking activity, we focus on an insulator containing the paused wingless (wg) promoter, and find that depleting RNA polymerase II (Pol II) binding has no effect on its insulator function; instead, the insulator binding proteins GAF and ELBA as well as their cognate DNA motifs are essential. We therefore conclude that active transcription or Pol II pausing is not a general mechanism required for enhancer blocking and that the insulator activity is mainly conferred by insulator proteins.
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| 8. |
- Vaid, Roshan, 1987-, et al.
(författare)
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Release of promoter–proximal paused Pol II in response to histone deacetylase inhibition
- 2020
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 48:9, s. 4877-4890
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Tidskriftsartikel (refereegranskat)abstract
- A correlation between histone acetylation and transcription has been noted for a long time, but little is known about what step(s) in the transcription cycle is influenced by acetylation. We have examined the immediate transcriptional response to histone deacetylase (HDAC) inhibition, and find that release of promoter–proximal paused RNA polymerase II (Pol II) into elongation is stimulated, whereas initiation is not. Although histone acetylation is elevated globally by HDAC inhibition, less than 100 genes respond within 10 min. These genes are highly paused, are strongly associated with the chromatin regulators NURF and Trithorax, display a greater increase in acetylation of the first nucleosomes than other genes, and become transcriptionally activated by HDAC inhibition. Among these rapidly up-regulated genes are HDAC1 (Rpd3) and subunits of HDAC-containing co-repressor complexes, demonstrating feedback regulation upon HDAC inhibition. Our results suggest that histone acetylation stimulates transcription of paused genes by release of Pol II into elongation, and that increased acetylation is not a consequence of their enhanced expression. We propose that HDACs are major regulators of Pol II pausing and that this partly explains the presence of HDACs at active genes.
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