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H2AZ Orchestrates Neural Progenitor Cell Proliferation and Differentiation via Setd2-mediated H3K36me3 Modification [ChIP-seq]

ABSTRACT: We report the genomic characterization of H2AZ binding at E13 brain. ChIP experiment was performed with antibody against H2AZ. we generated genome-wide characterization of H2AZ occupancy and find that H2AZ was prone to bind the promoter and the intergenic regions. The genomic localization of H2AZ might reveal its essential role during early neurogenesis. Gene ontology (GO) analysis, revealing that these genes occupied by H2AZ play roles in the cellular metabolic process, DNA replication, cell cycle, and neuron development and so on. Detailed investigation of the binding profiles show that direct binding of NkX2-4 by H2AZ. This study provides a framework for the epigenetic regulation of H2AZ in embryonic neurogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE99348 | GEO | 2017/05/29

SECONDARY ACCESSION(S): PRJNA388169

REPOSITORIES: GEO

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H2AZ Orchestrates Neural Progenitor Cell Proliferation and Differentiation via Setd2-mediated H3K36me3 Modification [RNA-seq]

Project description:Purpose:To gain a deeper insight into how H2AZ regulates embryonic neurogenesis, RNA-sequencing (RNA-seq) was performed to analyze the genome-wide changes by H2AZ deletion at E12. Methods: Total RNA was extracted from E12 telencephalic tissue of H2AZcKO and H2AZfl/fl mice. Then total RNA was quality controlled and quantified using an Agilent 2100 Bioanalyzer. After converting to cDNA and building library, high-throughput sequencing was performed using the Illumina HiSeq 2500 platform in Annoroad Genomics. Results: Approximately approximately one thousand transcripts showed differential expression between the H2AZfl/fl and H2AZcKO brain, with a fold change ≥1.5 and p value <0.05. Gene ontology (GO) analysis showed that the down-regulated genes were enriched in the terms related to transcription and cortex development, such as regulation of transcription, cerebellar cortex formation, forebrain development, and cerebellum development. Up-regulated genes showed a significant enrichment of terms involved in negative regulation of cell differentiation, neuron migration, and cognition. These results reflected the importance of H2AZ in cortical development. Conclusions: We conclude that RNA-seq based transcriptome characterization would provide a framework for understanding how a disruption in the H2AZ gene may contribute to cortical development.

2017-05-29 | GSE99347 | GEO

H2AZ extended acidic patch is necessary for formation specialized chromatin states in ESCs [RNA-Seq]

Project description:The H2A variant H2AZ is essential for embryonic development and for proper execution of developmental gene expression programs in embryonic stem cells (ESCs). Divergent regions in H2AZ are likely key for its functional specialization, but we know little about how these differences contribute to chromatin regulation. Here, we show that the extended acidic patch, specifically the three divergent residues in the C-terminal docking domain, is necessary for lineage commitment during ESC differentiation and proper execution of gene expression programs during ESC differentiation. Surprisingly, disruption of the acidic patch domain has a distinct consequence on cellular specification compared to H2AZ depletion. This is consistent with differences in gene expression profiles of H2AZ M-bM-^@M-^Sdepleted and acidic patch (AP) mutant ESCs during early lineage commitment. Interestingly, the distinct consequence of AP mutant expression on gene regulation is coincidence with an altered destabilized chromatin state and high chromatin mobility dependent on active transcription. Collectively, our data shows that the divergent residues within the acidic patch domain are key structural determinants of H2AZ function and links chromatin structure and dynamics with gene regulation and cell fate specification. H2AZ extended acidic patch was mutated, or H2AZ was KD in mouse embryonic stem cells and RNA-Seq analysis was performed on the resulting cultures. Characterization of H2AZ-WT and -AP3-mutant binding specificities were performed by ChIP-Seq.

2013-09-23 | E-GEOD-40064 | biostudies-arrayexpress

H2AZ extended acidic patch is necessary for formation specialized chromatin states in ESCs [ChIP-Seq]

2013-09-23 | E-GEOD-40063 | biostudies-arrayexpress

Chromatin immunopreciptiation of H2AZ in mouse embryonic stem cells and neural precursor cells

Project description:Elucidating how chromatin organization influences gene expression patterns and ultimately cell fate is fundamental to understanding development and disease. Histone variants have emerged as key regulators of genome function by creating specialized chromatin domains. The histone variant H2AZ plays an essential, but poorly understood function during early mammalian development. Genome-wide analysis reveals that H2AZ is enriched at a large class of developmentally important genes that are known targets of Polycomb-mediated repression in embryonic stem (ES) cells. H2AZ displays a highly defined spatial patterning that is remarkably similar to the Polycomb group (PcG) protein Suz12 in ES cells, but not in differentiated cell types. By using RNA interference, we demonstrate that H2AZ is a critical regulatory component at developmental genes in ES cells and show that localization of H2AZ and PcG proteins is interdependent at target promoters. Moreover, similarly to Suz12, H2AZ is required for lineage commitment. This study reveals a connection between H2AZ and PcG proteins in ES cells and suggests that these factors functionally interact to regulate chromatin states necessary for the proper execution of developmental gene expression programs.

2009-01-22 | E-TABM-556 | biostudies-arrayexpress

SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia.

Project description:Previously, we identified SETD2 loss-of-function mutations in 22% of MLL-rearranged (MLLr) acute leukemia patients, implicating a mechanism for cooperativity between SETD2 mutations and MLL fusions. However, the detailed mechanism of how SETD2-H3K36me3 downregulation accelerates MLLr leukemia remains unclear. Here, we show that in MLLr leukemia, both H3K79me2 and H3K36me3 are aberrantly elevated and co-enriched in a group of genes. SETD2 inactivation leads to a global reduction of H3K36me3 and a further elevation of H3K79me2, but does not change the expression of known MLL fusion target genes. Instead, this pattern of histone changes is associated with transcriptional deregulation of a novel set of genes; downregulating tumor suppressors (for example, ASXL1) and upregulating oncogenes (for example, ERG). Taken together, our findings reveal a global crosstalk between the oncogenic DOT1L-H3K79me2 axis and the tumor suppressive SETD2-H3K36me3 axis in gene regulation, provide molecular insights into how SETD2 mutations accelerate MLLr leukemogenesis through differential regulation of additional tumor suppressors and oncogenes.

| S-EPMC6277029 | biostudies-literature

SPOP-containing complex regulates SETD2 stability and H3K36me3-coupled alternative splicing.

Project description:Trimethylation of histone H3K36 is a chromatin mark associated with active gene expression, which has been implicated in coupling transcription with mRNA splicing and DNA damage response. SETD2 is a major H3K36 trimethyltransferase, which has been implicated as a tumor suppressor in mammals. Here, we report the regulation of SETD2 protein stability by the proteasome system, and the identification of SPOP, a key subunit of the CUL3 ubiquitin E3 ligase complex, as a SETD2-interacting protein. We demonstrate that SPOP is critically involved in SETD2 stability control and that the SPOP/CUL3 complex is responsible for SETD2 polyubiquitination both in vivo and in vitro ChIP-Seq analysis and biochemical experiments demonstrate that modulation of SPOP expression confers differential H3K36me3 on SETD2 target genes, and induce H3K36me3-coupled alternative splicing events. Together, these findings establish a functional connection between oncogenic SPOP and tumor suppressive SETD2 in the dynamic regulation of gene expression on chromatin.

| S-EPMC5224501 | biostudies-literature

Detection of H2AZ acetylation, total H2AZ, and H4K8 and H4K16 acetylation by CUT&Tag-sequencing

Project description:Detection of H2AZ acetylation, total H2AZ, and H4K8 and H4K16 acetylation by CUT&Tag-sequencing

| PRJNA859780 | ENA

H2AZ extended acidic patch is necessary for formation specialized chromatin states in ESCs [RNA-Seq]

Project description:The H2A variant H2AZ is essential for embryonic development and for proper execution of developmental gene expression programs in embryonic stem cells (ESCs). Divergent regions in H2AZ are likely key for its functional specialization, but we know little about how these differences contribute to chromatin regulation. Here, we show that the extended acidic patch, specifically the three divergent residues in the C-terminal docking domain, is necessary for lineage commitment during ESC differentiation and proper execution of gene expression programs during ESC differentiation. Surprisingly, disruption of the acidic patch domain has a distinct consequence on cellular specification compared to H2AZ depletion. This is consistent with differences in gene expression profiles of H2AZ –depleted and acidic patch (AP) mutant ESCs during early lineage commitment. Interestingly, the distinct consequence of AP mutant expression on gene regulation is coincidence with an altered destabilized chromatin state and high chromatin mobility dependent on active transcription. Collectively, our data shows that the divergent residues within the acidic patch domain are key structural determinants of H2AZ function and links chromatin structure and dynamics with gene regulation and cell fate specification.

2013-09-23 | GSE40064 | GEO

H2AZ extended acidic patch is necessary for formation specialized chromatin states in ESCs [ChIP-Seq]

Project description:The H2A variant H2AZ is essential for embryonic development and for proper execution of developmental gene expression programs in embryonic stem cells (ESCs). Divergent regions in H2AZ are likely key for its functional specialization, but we know little about how these differences contribute to chromatin regulation. Here, we show that the extended acidic patch, specifically the three divergent residues in the C-terminal docking domain, is necessary for lineage commitment during ESC differentiation and proper execution of gene expression programs during ESC differentiation. Surprisingly, disruption of the acidic patch domain has a distinct consequence on cellular specification compared to H2AZ depletion. This is consistent with differences in gene expression profiles of H2AZ –depleted and acidic patch (AP) mutant ESCs during early lineage commitment. Interestingly, the distinct consequence of AP mutant expression on gene regulation is coincidence with an altered destabilized chromatin state and high chromatin mobility dependent on active transcription. Collectively, our data shows that the divergent residues within the acidic patch domain are key structural determinants of H2AZ function and links chromatin structure and dynamics with gene regulation and cell fate specification.

2013-09-23 | GSE40063 | GEO

Regulation of SETD2 stability is important for the fidelity of H3K36me3 deposition.

Project description:BACKGROUND:The histone H3K36me3 mark regulates transcription elongation, pre-mRNA splicing, DNA methylation, and DNA damage repair. However, knowledge of the regulation of the enzyme SETD2, which deposits this functionally important mark, is very limited. RESULTS:Here, we show that the poorly characterized N-terminal region of SETD2 plays a determining role in regulating the stability of SETD2. This stretch of 1-1403 amino acids contributes to the robust degradation of SETD2 by the proteasome. Besides, the SETD2 protein is aggregate prone and forms insoluble bodies in nuclei especially upon proteasome inhibition. Removal of the N-terminal segment results in the stabilization of SETD2 and leads to a marked increase in global H3K36me3 which, uncharacteristically, happens in a Pol II-independent manner. CONCLUSION:The functionally uncharacterized N-terminal segment of SETD2 regulates its half-life to maintain the requisite cellular amount of the protein. The absence of SETD2 proteolysis results in a Pol II-independent H3K36me3 deposition and protein aggregation.

| S-EPMC7542105 | biostudies-literature

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