NSD1 mutations in Sotos Syndrome induce differential expression of long non-coding RNAs, miR646 and genes controlling the G2/M checkpoint
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ABSTRACT:
PROVIDER: PRJNA842248 | ENA |
REPOSITORIES: ENA
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Project description:An increasing amount of evidence indicates the critical role of NSD1 gene in the Sotos syndrome (SoS) and tumor. Molecular mechanisms affected by NSD1 mutations are largely uncharacterized. In order to assess the impact of NSD1 haploinsufficiency in the pathogenesis of SoS, we analyzed the gene expression profile of fibroblasts isolated from the skin sample of 15 SoS patients and from 5 healthy parents. We identified 7 differentially expressed genes and 5 differentially expressed non-coding RNAs. The most up-regulated mRNA was stratifin (SFN) (fold change, 3.9, p<0.05) and the most down-regulated mRNA was goosecoid homeobox (GSC) (fold change, 3.9, p<0.05).
2022-08-03 | GSE204775 | GEO
Project description:Genome-wide expression studies were performed on dermal fibroblasts from Sotos syndrome patients with a confirmed NSD1 abnormality and compared with age-sex matched controls. We used microarrays to detect differentially expressed genes in Sotos syndrome patients and performed a global test with the aim to map NSD1 within a signaling transduction pathway. Dermal fibroblasts were obtained from nine Sotos syndrome patients and nine controls. Since NSD1 is a co-factor of the retinoic acid receptor, cultures were performed both in the presence and absence of retinoic acid.
2014-02-06 | E-GEOD-27200 | biostudies-arrayexpress
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 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 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
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 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 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 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:An increasing amount of evidence indicates the critical role of the NSD1 gene in Sotos syndrome (SoS), a rare genetic disease, and in tumors. Molecular mechanisms affected by NSD1 mutations are largely uncharacterized. In order to assess the impact of NSD1 haploinsufficiency in the pathogenesis of SoS, we analyzed the gene expression profile of fibroblasts isolated from the skin samples of 15 SoS patients and of 5 healthy parents. We identified seven differentially expressed genes and five differentially expressed noncoding RNAs. The most upregulated mRNA was stratifin (SFN) (fold change, 3.9, Benjamini-Hochberg corrected p < 0.05), and the most downregulated mRNA was goosecoid homeobox (GSC) (fold change, 3.9, Benjamini-Hochberg corrected p < 0.05). The most upregulated lncRNA was lnc-C2orf84-1 (fold change, 4.28, Benjamini-Hochberg corrected p < 0.001), and the most downregulated lncRNA was Inc-C15orf57 (fold change, -0.7, Benjamini-Hochberg corrected p < 0.05). A gene set enrichment analysis reported the enrichment of genes involved in the KRAS and E2F signaling pathways, splicing regulation and cell cycle G2/M checkpoints. Our results suggest that NSD1 is involved in cell cycle regulation and that its mutation can induce the down-expression of genes involved in tumoral and neoplastic differentiation. The results contribute to defining the role of NSD1 in fibroblasts for the prevention, diagnosis and control of SoS.
| S-EPMC9324496 | biostudies-literature