| 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. |
- 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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| 4. |
- 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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