The Sotos syndrome gene Nsd1 safeguards bivalent developmental enhancers in poised states through restraining excessive H3K27me3 deposition [Cut & Tag]
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ABSTRACT:
PROVIDER: PRJNA1133764 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29758215_1.fastq.gz | Fastqsanger.gz | |||
| SRR29758215_2.fastq.gz | Fastqsanger.gz |
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Project description:Germline haploinsufficiency of Nsd1 is implicated as the etiology of Sotos syndrome, a developmental genetic disorder manifesting skeletal overgrowth and intellectual disability. However, the underlying molecular mechanisms remain largely elusive to date. Here we employed mouse embryonic stem (ES) cell in vitro differentiation as a developmental model system to tackle this question. We found that Nsd1 is indispensable for faithful differentiation of mouse ES cells into three primary germ layers, particularly the meso-endoderm lineages such as heart, vascular, and skeletal systems. Time-series gene expression profiling revealed that Nsd1 facilitates not only the basal expression but also differentiation-accompanied rapid induction of certain key meso-endoderm linage-specifying transcription factor genes such as T and Gata4. Mechanistically, Nsd1 directly binds to putative distal bivalent enhancers of these genes under ES state, where it antagonizes excessive H3K27me3 through depositing H3K36me2 and conversely maintains the active H3K27ac mark, thereby safeguarding these enhancers at poised or primed states that are highly responsive to developmental cues. In agreement, rescue assays showed that Nsd1-catalyzed H3K36me2 depends on intact PHD1-4, PWWP2, and SET domains to a similar degree, disruption of either one severely abolished Nsd1’s ability to revert the defective differentiation phenotype. Additionally, Nsd1 is likely continuously required to sustain the activation of certain developmental genes, as it continues to reside at these genes after differentiation induction, albeit recruited by a different set of transcription factors. Altogether, our results provide novel molecular insights into how Nsd1 perturbations derail the normal developmental pathways and cause human disease.
2025-02-25 | GSE271862 | GEO
Project description:Germline haploinsufficiency of Nsd1 is implicated as the etiology of Sotos syndrome, a developmental genetic disorder manifesting skeletal overgrowth and intellectual disability. However, the underlying molecular mechanisms remain largely elusive to date. Here we employed mouse embryonic stem (ES) cell in vitro differentiation as a developmental model system to tackle this question. We found that Nsd1 is indispensable for faithful differentiation of mouse ES cells into three primary germ layers, particularly the meso-endoderm lineages such as heart, vascular, and skeletal systems. Time-series gene expression profiling revealed that Nsd1 facilitates not only the basal expression but also differentiation-accompanied rapid induction of certain key meso-endoderm linage-specifying transcription factor genes such as T and Gata4. Mechanistically, Nsd1 directly binds to putative distal bivalent enhancers of these genes under ES state, where it antagonizes excessive H3K27me3 through depositing H3K36me2 and conversely maintains the active H3K27ac mark, thereby safeguarding these enhancers at poised or primed states that are highly responsive to developmental cues. In agreement, rescue assays showed that Nsd1-catalyzed H3K36me2 depends on intact PHD1-4, PWWP2, and SET domains to a similar degree, disruption of either one severely abolished Nsd1’s ability to revert the defective differentiation phenotype. Additionally, Nsd1 is likely continuously required to sustain the activation of certain developmental genes, as it continues to reside at these genes after differentiation induction, albeit recruited by a different set of transcription factors. Altogether, our results provide novel molecular insights into how Nsd1 perturbations derail the normal developmental pathways and cause human disease.
2025-02-25 | GSE271861 | GEO
Project description:Germline haploinsufficiency of Nsd1 is implicated as the etiology of Sotos syndrome, a developmental genetic disorder manifesting skeletal overgrowth and intellectual disability. However, the underlying molecular mechanisms remain largely elusive to date. Here we employed mouse embryonic stem (ES) cell in vitro differentiation as a developmental model system to tackle this question. We found that Nsd1 is indispensable for faithful differentiation of mouse ES cells into three primary germ layers, particularly the meso-endoderm lineages such as heart, vascular, and skeletal systems. Time-series gene expression profiling revealed that Nsd1 facilitates not only the basal expression but also differentiation-accompanied rapid induction of certain key meso-endoderm linage-specifying transcription factor genes such as T and Gata4. Mechanistically, Nsd1 directly binds to putative distal bivalent enhancers of these genes under ES state, where it antagonizes excessive H3K27me3 through depositing H3K36me2 and conversely maintains the active H3K27ac mark, thereby safeguarding these enhancers at poised or primed states that are highly responsive to developmental cues. In agreement, rescue assays showed that Nsd1-catalyzed H3K36me2 depends on intact PHD1-4, PWWP2, and SET domains to a similar degree, disruption of either one severely abolished Nsd1’s ability to revert the defective differentiation phenotype. Additionally, Nsd1 is likely continuously required to sustain the activation of certain developmental genes, as it continues to reside at these genes after differentiation induction, albeit recruited by a different set of transcription factors. Altogether, our results provide novel molecular insights into how Nsd1 perturbations derail the normal developmental pathways and cause human disease.
2025-02-25 | GSE271864 | GEO
Project description:The Sotos syndrome gene Nsd1 safeguards bivalent developmental enhancers in poised states through restraining excessive H3K27me3 deposition [RNA-Seq]
| PRJNA1133766 | ENA
Project description:The Sotos syndrome gene Nsd1 safeguards bivalent developmental enhancers in poised states through restraining excessive H3K27me3 deposition [ChIP-seq]
| PRJNA1133767 | ENA
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 | 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 | GSE208682 | GEO