Study of three-dimensional structure of chromatin through a 4C-seq experiment in mouse NSC shControl and shJMJD3 upon TGFβ treatment [Ldlrad4]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE197012 | GEO | 2022/04/21
REPOSITORIES: GEO
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Project description:In this study we analyzed how multiple enhancers arrange in the 3D-space to control the activation of a specific promoter. Specifically, we did three 4C-seq experiments on different genomic loci where enhancers abound - Chst8, Ldlrad4 and Aopep, which revealed that the TGFβ pathway drives the establishment of contacts between cis-regulatory elements. Furthermore, we discovered that the TGFβ pathway coactivator JMJD3 is essential to maintain these 3D-structures. Specifically, in the Chst8 locus JMJD3 requires a proline-rich intrinsically disordered region to properly induce these loops, and hence gene activation, due to its involvement in the formation of phase-separated biomolecular condensates. Overall, we uncover novel functions for the ubiquitous coactivator JMJD3, and we shed light on the relationships between the 3D-conformation of the chromatin, and their role in regulating the TGFβ-driven response during mammalian neurogenesis.
2022-04-21 | GSE197011 | GEO
Project description:In this study we analyzed how multiple enhancers arrange in the 3D-space to control the activation of a specific promoter. Specifically, we did a 4C-seq experiment on a ~374 Kb locus where enhancers abound, which revealed that the TGFβ pathway drives the establishment of contacts between cis-regulatory elements that facilitates the assembly of an enhancer-cluster and precise gene activation. We discovered that the TGFβ pathway coactivator JMJD3 is essential to maintain these 3D-structures, as when it is depleted the contacts are lost but they are restablished when re-expressing the protein. To do that, JMJD3 requires a proline-rich intrinsically disordered region, which is essential for proper gene activation due to its involvement in the formation of phase-separated biomolecular condensates. Overall, we uncover novel functions for the ubiquitous coactivator JMJD3, and we shed light on the relationships between the 3D-conformation of the chromatin, and their role in regulating the TGFβ-driven response during mammalian neurogenesis.
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Project description:Neural development requires crosstalk between signaling pathways and chromatin. In this study, we demonstrate that neurogenesis is promoted by an interplay between the TGFβ pathway and the H3K27me3 histone demethylase (HDM) JMJD3. Genome-wide analysis showed that JMJD3 is targeted to gene promoters by Smad3 in neural stem cells (NSCs) and is essential to activate TGFβ-responsive genes. In vivo experiments in chick spinal cord revealed that the generation of neurons promoted by Smad3 is dependent on JMJD3 HDM activity. Overall, these findings indicate that JMJD3 function is required for the TGFβ developmental program to proceed
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Project description:Neural development requires crosstalk between signaling pathways and chromatin. In this study, we demonstrate that neurogenesis is promoted by an interplay between the TGFβ pathway and the H3K27me3 histone demethylase (HDM) JMJD3. Genome-wide analysis showed that JMJD3 is targeted to gene promoters by Smad3 in neural stem cells (NSCs) and is essential to activate TGFβ-responsive genes. In vivo experiments in chick spinal cord revealed that the generation of neurons promoted by Smad3 is dependent on JMJD3 HDM activity. Overall, these findings indicate that JMJD3 function is required for the TGFβ developmental program to proceed.
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Project description:Several signaling pathways require JMJD3 binding to promoters to activate the expression of target genes. Despite the known H3K27me3 demethylase activity of JMJD3 the transcriptional coactivator mechanism remains unclear. Here we reveal that JMJD3 promotes transcription of TGFb responsive genes through regulation of RNAPII progression on gene bodies. ChIPseq experiments demonstrate that upon TGFb treatment, JMJD3 and RNAPII.ser2P colocalyze extensively along intragenic regions of TGF target genes. M-BM- According to these data, genome wide analysis shows that JMJD3 dependent TGF target genes are enriched in H3K27me3 prior to TGF signaling pathway activation. M-BM- Further molecular analysis indicate that JMJD3 removes H3K27me3 and pave the way for the RNAPII.Overall, these findingsM-BM- uncover the mechanism ofM-BM- JMJD3 function in transcriptional activation We performed chromatin immunoprecipitation followed by sequencing (ChIPseq) of H3K27me3 mark in mouse neural stem cells growing under standard conditions. We also performed ChIPseq of elongating RNAPII (Ser2P) and JMJD3 in neural stem cells stimulated with TGFb cytokine.
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Project description:Several signaling pathways require JMJD3 binding to promoters to activate the expression of target genes. Despite the known H3K27me3 demethylase activity of JMJD3 the transcriptional coactivator mechanism remains unclear. Here we reveal that JMJD3 promotes transcription of TGFb responsive genes through regulation of RNAPII progression on gene bodies. ChIPseq experiments demonstrate that upon TGFb treatment, JMJD3 and RNAPII.ser2P colocalyze extensively along intragenic regions of TGF target genes. According to these data, genome wide analysis shows that JMJD3 dependent TGF target genes are enriched in H3K27me3 prior to TGF signaling pathway activation. Further molecular analysis indicate that JMJD3 removes H3K27me3 and pave the way for the RNAPII.Overall, these findings uncover the mechanism of JMJD3 function in transcriptional activation
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Project description:TGFβ cytokines have crucial roles in development, proliferation, tissue homeostasis, differentiation, and immune regulation. Consequently, alterations in TGFβ signaling underlie numerous diseases, including cancer. Moreover TGFβ is one of the most potent inductors of EMT (epithelial to mesenchymal transition) in normal and oncogenic epithelial cells from different origins. During EMT, cells undergo an extensive reorganization of cell adhesion complexes, cytoskeletal architecture, and extracellular matrix interactions and acquire increased motility and invasion properties. However, little is known about the genomic repertoire of enhancers activated by TGFβ, the chromatin dynamics during this process, or the SMAD (main effectors of TGFβ pathway) partners in epithelial cells. To address these outstanding questions about the genomic regulation mediated by TGFβ in epithelial cells we determine and characterize the enhancer atlas of the TGFβ response in normal murine mammary gland (NMuMG) epithelial cells, a well-established model for TGFβ-dependent EMT. To achieve this we performed ATAC-seq, ChIP-seq against typical histone modifications for enhancers and promoters (H3K27ac, H3K4me1 and H3K4me3) and ChromRNA-seq (to identify enhancer RNAs) analyses at two different time points after TGFβ treatment (2h and 12h) to study the enhancers dynamics during this process. We also performed a transcriptomic analyses (RNA-seq) at same time points to correlate genomic regulation to transcriptional changes upon TGFβ treatment. We show that TGFβ promotes a fast and widespread increase of chromatin accessibility in most enhancers of the cell line, irrespectively of whether the enhancer will become activated or repressed. We also observed that activated enhancers are strongly enriched for SMAD2/3/4 and AP-1 footprints. In contrast, decommissioned enhancers present footprints for TEAD, HNF1A, or HNF1B TF (and not for SMAD2/3/4). Strikingly, analyses of the regulated genes around TGFβ-regulated enhancers revealed TGFβ regulatory domains that can encompass several genes and that are constrained by 3D chromatin conformation. In these domains enhancer targeting is more promiscuous than previously anticipated.
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Project description:TGFβ cytokines have crucial roles in development, proliferation, tissue homeostasis, differentiation, and immune regulation. Consequently, alterations in TGFβ signaling underlie numerous diseases, including cancer. Moreover TGFβ is one of the most potent inductors of EMT (epithelial to mesenchymal transition) in normal and oncogenic epithelial cells from different origins. During EMT, cells undergo an extensive reorganization of cell adhesion complexes, cytoskeletal architecture, and extracellular matrix interactions and acquire increased motility and invasion properties. However, little is known about the genomic repertoire of enhancers activated by TGFβ, the chromatin dynamics during this process, or the SMAD (main effectors of TGFβ pathway) partners in epithelial cells. To address these outstanding questions about the genomic regulation mediated by TGFβ in epithelial cells we determine and characterize the enhancer atlas of the TGFβ response in normal murine mammary gland (NMuMG) epithelial cells, a well-established model for TGFβ-dependent EMT. To achieve this we performed ATAC-seq, ChIP-seq against typical histone modifications for enhancers and promoters (H3K27ac, H3K4me1 and H3K4me3) and ChromRNA-seq (to identify enhancer RNAs) analyses at two different time points after TGFβ treatment (2h and 12h) to study the enhancers dynamics during this process. We also performed a transcriptomic analyses (RNA-seq) at same time points to correlate genomic regulation to transcriptional changes upon TGFβ treatment. We show that TGFβ promotes a fast and widespread increase of chromatin accessibility in most enhancers of the cell line, irrespectively of whether the enhancer will become activated or repressed. We also observed that activated enhancers are strongly enriched for SMAD2/3/4 and AP-1 footprints. In contrast, decommissioned enhancers present footprints for TEAD, HNF1A, or HNF1B TF (and not for SMAD2/3/4). Strikingly, analyses of the regulated genes around TGFβ-regulated enhancers revealed TGFβ regulatory domains that can encompass several genes and that are constrained by 3D chromatin conformation. In these domains enhancer targeting is more promiscuous than previously anticipated.
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Project description:TGFβ cytokines have crucial roles in development, proliferation, tissue homeostasis, differentiation, and immune regulation. Consequently, alterations in TGFβ signaling underlie numerous diseases, including cancer. Moreover TGFβ is one of the most potent inductors of EMT (epithelial to mesenchymal transition) in normal and oncogenic epithelial cells from different origins. During EMT, cells undergo an extensive reorganization of cell adhesion complexes, cytoskeletal architecture, and extracellular matrix interactions and acquire increased motility and invasion properties. However, little is known about the genomic repertoire of enhancers activated by TGFβ, the chromatin dynamics during this process, or the SMAD (main effectors of TGFβ pathway) partners in epithelial cells. To address these outstanding questions about the genomic regulation mediated by TGFβ in epithelial cells we determine and characterize the enhancer atlas of the TGFβ response in normal murine mammary gland (NMuMG) epithelial cells, a well-established model for TGFβ-dependent EMT. To achieve this we performed ATAC-seq, ChIP-seq against typical histone modifications for enhancers and promoters (H3K27ac, H3K4me1 and H3K4me3) and ChromRNA-seq (to identify enhancer RNAs) analyses at two different time points after TGFβ treatment (2h and 12h) to study the enhancers dynamics during this process. We also performed a transcriptomic analyses (RNA-seq) at same time points to correlate genomic regulation to transcriptional changes upon TGFβ treatment. We show that TGFβ promotes a fast and widespread increase of chromatin accessibility in most enhancers of the cell line, irrespectively of whether the enhancer will become activated or repressed. We also observed that activated enhancers are strongly enriched for SMAD2/3/4 and AP-1 footprints. In contrast, decommissioned enhancers present footprints for TEAD, HNF1A, or HNF1B TF (and not for SMAD2/3/4). Strikingly, analyses of the regulated genes around TGFβ-regulated enhancers revealed TGFβ regulatory domains that can encompass several genes and that are constrained by 3D chromatin conformation. In these domains enhancer targeting is more promiscuous than previously anticipated.
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