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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.
2023-07-05 | GSE236028 | 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 a spectrum of cancers and the genetic disorder Sotos syndrome. Despite its function in modulating the chromatin landscape, 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, in a cell type-specific manner. NSD1 enhancer association is conferred by its tandem quadruple PHD-PWWP domain, which is a hotspot for Sotos syndrome missense mutations. By combining acute NSD1 depletion with temporally resolved epigenomic and nascent transcriptomic analysis, we demonstrate that NSD1/H3K36me2 plays a critical role in facilitating enhancer-dependent gene transcription by promoting promoter pause release of RNA polymerase II. Moreover, NSD1 regulates ESC multilineage differentiation through facilitating transcriptional activation of critical developmental programs implicated in Sotos syndrome pathogenesis. Collectively, we have identified NSD1 as a novel enhancer-acting transcriptional coactivator and provided mechanistic insights into its contribution to cell fate transition and association with a human developmental disorder.
2023-07-05 | GSE208670 | 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 a spectrum of cancers and the genetic disorder Sotos syndrome. Despite its function in modulating the chromatin landscape, 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, in a cell type-specific manner. NSD1 enhancer association is conferred by its tandem quadruple PHD-PWWP domain, which is a hotspot for Sotos syndrome missense mutations. By combining acute NSD1 depletion with temporally resolved epigenomic and nascent transcriptomic analysis, we demonstrate that NSD1/H3K36me2 plays a critical role in facilitating enhancer-dependent gene transcription by promoting promoter pause release of RNA polymerase II. Moreover, NSD1 regulates ESC multilineage differentiation through facilitating transcriptional activation of critical developmental programs implicated in Sotos syndrome pathogenesis. Collectively, we have identified NSD1 as a novel enhancer-acting transcriptional coactivator and provided mechanistic insights into its contribution to cell fate transition and association with a human developmental disorder.
2023-07-05 | GSE208607 | 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.
2023-07-05 | GSE208604 | 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.
2023-07-05 | GSE236029 | 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 a spectrum of cancers and the genetic disorder Sotos syndrome. Despite its function in modulating the chromatin landscape, 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, in a cell type-specific manner. NSD1 enhancer association is conferred by its tandem quadruple PHD-PWWP domain, which is a hotspot for Sotos syndrome missense mutations. By combining acute NSD1 depletion with temporally resolved epigenomic and nascent transcriptomic analysis, we demonstrate that NSD1/H3K36me2 plays a critical role in facilitating enhancer-dependent gene transcription by promoting promoter pause release of RNA polymerase II. Moreover, NSD1 regulates ESC multilineage differentiation through facilitating transcriptional activation of critical developmental programs implicated in Sotos syndrome pathogenesis. Collectively, we have identified NSD1 as a novel enhancer-acting transcriptional coactivator and provided mechanistic insights into its contribution to cell fate transition and association with a human developmental disorder.
2023-07-05 | GSE208694 | 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.
2023-07-05 | GSE208682 | GEO
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