Effect of depletion of Nsd1 or Ezh2 on gene expression during pluripotency transition
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE334791 | GEO | 2026/07/15
REPOSITORIES: GEO
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Project description:Disruption of antagonism between SWI/SNF chromatin remodelers and Polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of Polycomb protein EZH2 was approved for treatment of sarcomas mutant in SWI/SNF subunit SMARCB1, but resistance occurs. Here we sought to identify additional contributors to SWI/SNF-Polycomb antagonism and potential resistance mechanisms. We performed CRISPR screens and found that NSD1 loss caused resistance to EZH2 inhibition. NSD1 loss reduced H3K36me2 and impaired transcriptional activation of targets inhibited by EZH2 or activated by SMARCB1. Further, inhibiting the H3K36me2 demethylase KDM2A restored EZH2 inhibition in cells lacking NSD1. Our results expand the mechanistic understanding of SWI/SNF and Polycomb interplay and identify NSD1 as key for coordinating this transcriptional control.
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Project description:Disruption of antagonism between SWI/SNF chromatin remodelers and Polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of Polycomb protein EZH2 was approved for treatment of sarcomas mutant in SWI/SNF subunit SMARCB1, but resistance occurs. Here we sought to identify additional contributors to SWI/SNF-Polycomb antagonism and potential resistance mechanisms. We performed CRISPR screens and found that NSD1 loss caused resistance to EZH2 inhibition. NSD1 loss reduced H3K36me2 and impaired transcriptional activation of targets inhibited by EZH2 or activated by SMARCB1. Further, inhibiting the H3K36me2 demethylase KDM2A restored EZH2 inhibition in cells lacking NSD1. Our results expand the mechanistic understanding of SWI/SNF and Polycomb interplay and identify NSD1 as key for coordinating this transcriptional control.
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Project description:The formation of the mammalian neocortex during development requires coordinated establishment of functional regions at proper anterior-posterior and medial-lateral positions – area patterning, as well as neocortical layers. Although key transcription factors (TFs) were known to specify and maintain cell fates, mechanisms underlying how TFs are precise expressed and repressed are largely elusive. Here we showed that NSD1, the methyltransferase for histone H3 lysine 36 dimethylation (H3K36me2), controls both areal and layer identities of the neocortex. Nsd1-ablated neocortex showed prominent areal shift of all four primary functional regions and aberrant wiring of major cortico-thalamic-cortical projections. Nsd1 conditional knockout mice displayed defects in spatial memory, motor learning and coordination, reminiscent of patients with the Sotos syndrome carrying NSD1 mutations. Although projection neurons (PN) of neocortical layers were mostly properly produced and positioned upon Nsd1 deletion, post-mitotic PNs could not establish their layer-specific identities. More strikingly, in adult Nsd1 conditional knockout neocortices, superficial-layer PNs progressively mis-expressed markers for deep-layer PNs. Moreover, neocortical PNs ablated with Nsd1 remained immature morphologically and electrophysiologically. Loss of NSD1 in post-mitotic PNs causes genome-wide loss of H3K36me2 and re-distribution of DNA methylation, which accounts for diminished expression of neocortical layer specifiers but ectopic expression of non-neural genes. Our findings revealed that H3K36me2 mediated by NSD1 is required for establishment and maintenance of region- and layer-specific neocortical identities.
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Project description:The formation of the mammalian neocortex during development requires coordinated establishment of functional regions at proper anterior-posterior and medial-lateral positions – area patterning, as well as neocortical layers. Although key transcription factors (TFs) were known to specify and maintain cell fates, mechanisms underlying how TFs are precise expressed and repressed are largely elusive. Here we showed that NSD1, the methyltransferase for histone H3 lysine 36 dimethylation (H3K36me2), controls both areal and layer identities of the neocortex. Nsd1-ablated neocortex showed prominent areal shift of all four primary functional regions and aberrant wiring of major cortico-thalamic-cortical projections. Nsd1 conditional knockout mice displayed defects in spatial memory, motor learning and coordination, reminiscent of patients with the Sotos syndrome carrying NSD1 mutations. Although projection neurons (PN) of neocortical layers were mostly properly produced and positioned upon Nsd1 deletion, post-mitotic PNs could not establish their layer-specific identities. More strikingly, in adult Nsd1 conditional knockout neocortices, superficial-layer PNs progressively mis-expressed markers for deep-layer PNs. Moreover, neocortical PNs ablated with Nsd1 remained immature morphologically and electrophysiologically. Loss of NSD1 in post-mitotic PNs causes genome-wide loss of H3K36me2 and re-distribution of DNA methylation, which accounts for diminished expression of neocortical layer specifiers but ectopic expression of non-neural genes. Our findings revealed that H3K36me2 mediated by NSD1 is required for establishment and maintenance of region- and layer-specific neocortical identities.
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Project description:The formation of the mammalian neocortex during development requires coordinated establishment of functional regions at proper anterior-posterior and medial-lateral positions – area patterning, as well as neocortical layers. Although key transcription factors (TFs) were known to specify and maintain cell fates, mechanisms underlying how TFs are precise expressed and repressed are largely elusive. Here we showed that NSD1, the methyltransferase for histone H3 lysine 36 dimethylation (H3K36me2), controls both areal and layer identities of the neocortex. Nsd1-ablated neocortex showed prominent areal shift of all four primary functional regions and aberrant wiring of major cortico-thalamic-cortical projections. Nsd1 conditional knockout mice displayed defects in spatial memory, motor learning and coordination, reminiscent of patients with the Sotos syndrome carrying NSD1 mutations. Although projection neurons (PN) of neocortical layers were mostly properly produced and positioned upon Nsd1 deletion, post-mitotic PNs could not establish their layer-specific identities. More strikingly, in adult Nsd1 conditional knockout neocortices, superficial-layer PNs progressively mis-expressed markers for deep-layer PNs. Moreover, neocortical PNs ablated with Nsd1 remained immature morphologically and electrophysiologically. Loss of NSD1 in post-mitotic PNs causes genome-wide loss of H3K36me2 and re-distribution of DNA methylation, which accounts for diminished expression of neocortical layer specifiers but ectopic expression of non-neural genes. Our findings revealed that H3K36me2 mediated by NSD1 is required for establishment and maintenance of region- and layer-specific neocortical identities.
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Project description:The core Polycomb Repressor Complex 2 (PRC2) is composed of Ezh1/2, Suz12, Eed and is responsible for mediating both H3K27me2 and H3K27me3. However, the mechanisms by which PRC2 demarcates these two repressive modifications in the genome are unknown. In a functional screen, we identified the H3K36 dimethyltransferase Nsd1 as a modulator of PRC2-mediated di- and trimethylation of H3K27. ChIP-Seq analysis following the depletion of Nsd1 revealed a global reduction in H3K36me2 and an increase in H3K27me3 at sites previously marked by H3K27me2. We show that the H3K36me2 at H3K27me2 marks co-occupy regions and provide evidence that the presence of H3K36me2 functions to restrict the spatial distribution of Polycomb mediated H3K27me3 domains.
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Project description:The core Polycomb Repressor Complex 2 (PRC2) is composed of Ezh1/2, Suz12, Eed and is responsible for mediating both H3K27me2 and H3K27me3. However, the mechanisms by which PRC2 demarcates these two repressive modifications in the genome are unknown. In a functional screen, we identified the H3K36 dimethyltransferase Nsd1 as a modulator of PRC2-mediated di- and trimethylation of H3K27. ChIP-Seq analysis following the depletion of Nsd1 revealed a global reduction in H3K36me2 and an increase in H3K27me3 at sites previously marked by H3K27me2. We show that the H3K36me2 at H3K27me2 marks co-occupy regions and provide evidence that the presence of H3K36me2 functions to restrict the spatial distribution of Polycomb mediated H3K27me3 domains.
2018-09-15 | GSE86925 | GEO
Project description:Nuclear-receptor-binding SET-domain protein 1 (NSD1), a methyltransferase that catalyzes H3K36me2, is essential for mammalian development and frequently dysregulated in diseases, including Sotos syndrome. Despite impacts of H3K36me2 on H3K27me3 and DNA methylation, a direct role of NSD1 in transcriptional regulation remains largely unknown. Here, we show that NSD1 and H3K36me2 are enriched at cis-regulatory elements, particularly enhancers. NSD1 enhancer association is conferred by a tandem quadruple PHD-PWWP module, which recognizes p300-catalyzed H3K18ac. By combining acute NSD1 depletion with time-resolved epigenomic and nascent transcriptomic analyses, we demonstrate that NSD1 promotes enhancer-dependent gene transcription by facilitating RNA polymerase II pause release. Notably, NSD1 can act as a transcriptional coactivator independent of its catalytic activity. Moreover, NSD1 enables activation of developmental transcriptional programs associated with Sotos syndrome pathophysiology and controls ESC multilineage differentiation. Collectively, we have identified NSD1 as an enhancer-acting transcriptional coactivator that contributes to cell fate transition and Sotos syndrome development.
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Project description:Epigenetics, especially histone marks, functions beyond the DNA sequences to regulate gene expression. Depletion of NSD1, which catalyzes H3K36me2, led to both up- and down-regulation of gene expression, indicating NSD1 is associated with both active and repressed gene expression. It’s known that NSD1 regulates the deposition and expansion of H3K27me3, a repressive mark for gene expression, to keep active gene transcription. However, how NSD1 functions to repress gene expression is largely unknown. Here, we found that, when NSD1 was knocked out in mouse embryonic stem cells (mESCs), H3K27ac increased correlatively with the decrease of H3K36me2 at active enhancers, which is associated with mesoderm differentiation genes, leading to elevated gene expression. Mechanistically, NSD1 recruits HDAC1, the deacetylase of H3K27ac, to chromatin. Moreover, HDAC1 knockout (KO) recapitulates the increase of H3K27ac at active enhancers as the NSD1 depletion. Together, we propose that NSD1 deposits H3K36me2 and recruits HDAC1 at active enhancers to serve as a ‘safeguard’, preventing further activation of active enhancer-associated genes.
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Project description:Nuclear-receptor-binding SET-domain protein 1 (NSD1), a methyltransferase that catalyzes H3K36me2, is essential for mammalian development and frequently dysregulated in diseases, including Sotos syndrome. Despite impacts of H3K36me2 on H3K27me3 and DNA methylation, a direct role of NSD1 in transcriptional regulation remains largely unknown. Here, we show that NSD1 and H3K36me2 are enriched at cis-regulatory elements, particularly enhancers. NSD1 enhancer association is conferred by a tandem quadruple PHD-PWWP module, which recognizes p300-catalyzed H3K18ac. By combining acute NSD1 depletion with time-resolved epigenomic and nascent transcriptomic analyses, we demonstrate that NSD1 promotes enhancer-dependent gene transcription by facilitating RNA polymerase II pause release. Notably, NSD1 can act as a transcriptional coactivator independent of its catalytic activity. Moreover, NSD1 enables activation of developmental transcriptional programs associated with Sotos syndrome pathophysiology and controls ESC multilineage differentiation. Collectively, we have identified NSD1 as an enhancer-acting transcriptional coactivator that contributes to cell fate transition and Sotos syndrome development.
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