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HP1γ regulates H3K36 methylation and pluripotency in embryonic stem cells (RNA-seq)

ABSTRACT: The heterochromatin protein 1 (HP1) family members are canonical effectors and propagators of gene repression mediated by histone H3 lysine 9 (H3K9) methylation. HP1γ exhibits an increased interaction with active transcription elongation-associated factors in embryonic stem cells (ESCs) compared to somatic cells. However, whether this association has a functional consequence remains elusive. Here we find that genic HP1γ colocalizes and enhances enrichment of transcription elongation-associated H3K36me3 rather than H3K9me3. Unexpectedly, sustained H3K36me3 deposition is dependent on HP1γ. HP1γ-deleted ESCs display reduced H3K36me3 enrichment, concomitant with decreased expression at shared genes which function to maintain cellular homeostasis. Both the H3K9me3-binding chromodomain and histone binding ability of HP1γ are dispensable for maintaining H3K36me3 levels. Instead, the chromoshadow together with the hinge domain of HP1γ that confer protein and nucleic acid-binding ability are sufficient because they retain the ability to interact with NSD1, an H3K36 methyltransferase. HP1γ-deleted ESCs have a slower self-renewal rate and an impaired ability to differentiate towards cardiac mesoderm. Our findings reveal a requirement for HP1γ in faithful establishment of transcription elongation in ESCs, which regulates pluripotency.

ORGANISM(S): Mus musculus

PROVIDER: GSE144862 | GEO | 2020/11/01

REPOSITORIES: GEO

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HP1γ regulates H3K36 methylation and pluripotency in embryonic stem cells (ChIP-Seq)

Project description:The heterochromatin protein 1 (HP1) family members are canonical effectors and propagators of gene repression mediated by histone H3 lysine 9 (H3K9) methylation. HP1γ exhibits an increased interaction with active transcription elongation-associated factors in embryonic stem cells (ESCs) compared to somatic cells. However, whether this association has a functional consequence remains elusive. Here we find that genic HP1γ colocalizes and enhances enrichment of transcription elongation-associated H3K36me3 rather than H3K9me3. Unexpectedly, sustained H3K36me3 deposition is dependent on HP1γ. HP1γ-deleted ESCs display reduced H3K36me3 enrichment, concomitant with decreased expression at shared genes which function to maintain cellular homeostasis. Both the H3K9me3-binding chromodomain and histone binding ability of HP1γ are dispensable for maintaining H3K36me3 levels. Instead, the chromoshadow together with the hinge domain of HP1γ that confer protein and nucleic acid-binding ability are sufficient because they retain the ability to interact with NSD1, an H3K36 methyltransferase. HP1γ-deleted ESCs have a slower self-renewal rate and an impaired ability to differentiate towards cardiac mesoderm. Our findings reveal a requirement for HP1γ in faithful establishment of transcription elongation in ESCs, which regulates pluripotency.

2020-11-01 | GSE144861 | GEO

Mouse HP1γ regulates TRF1 expression and telomere stability

Project description:Telomeric Repeat-containing RNA are long non-coding RNAs generated from the telomeres. TERRAs are essential for the establishment of heterochromatin marks at telomeres, which serve for the binding of members of the Heterochromatin Protein 1protein family of epigenetic modifiers involved with chromatin compaction and gene silencing. While HP1γ is enriched on gene bodies of actively transcribed mammalian genes, it is unclear if its transcriptional role is important for HP1γ function in telomere cohesion and telomere maintenance. We aimed to study the effect of mouse HP1γ on the transcription of telomere factors and molecules that can affect telomere maintenance. We investigated the telomere function of HP1γ by using HP1γ deficient mouse embryonic fibroblastsderiving from 13.5 embryonic day embryos compared to their littermate controls. We used gene expression analysis of HP1γ deficient MEFs and validated the molecular and mechanistic consequences of HP1γ loss by telomere FISH, immunofluorescence, RT-qPCR and DNA-RNA Immunoprecipitation. Loss of HP1γ in primary MEFs led to a downregulation of various telomere and telomere-accessory transcripts, including the shelterin protein TRF1. Its downregulation is associated with increased telomere replication stress and DNA damage (γH2AX), effects more profound in females. We suggest that the source for the impaired telomere maintenance is a consequence of increased telomeric DNARNA hybrids and TERRAs arising at and from mouse chromosomes 18 and X. Our results suggest an important transcriptional control by mouse HP1γ of various telomere factors including TRF1 protein and TERRAs that has profound consequences on telomere stability, with a potential sexually dimorphic nature.

2023-08-19 | GSE240434 | GEO

Knockdown of HP1γ in H1792 cells

Project description:For analysis of genes regulated by HP1γ in LUAD, we used microarray analysis to determine the global changes in gene expression upon HP1γ knockdown in H1792 cells and identified distinct sets of up-regulated and down-regulated genes upon depletion of HP1γ.

2018-11-13 | GSE111321 | GEO

Compartmentalization of HP1 proteins in pluripotency acquisition and maintenance

Project description:Embryonic stem cells (ESCs) have a hyperdynamic chromatin structure characterized by fewer discrete foci of heterochromatin protein 1 family of proteins (HP1) compared to somatic cells. During reprogramming of somatic cells, depletion of HP1γ early, reduced, while depletion later, enhanced the generation of induced pluripotent stem cells (iPSCs); concomitant with a change from a centromeric to nucleoplasmic localization. To identify the interactome of HP1γ in different biochemical environment in ESCs, we compared protein complexes of HP1γ at 0.42M salt (Dignam et al, 1983), with micrococcal nuclease (MCN) digestion with 0.3M NaCl, and MCN with 0.5M NaCl. To understand the effectors of the change in localization, we isolated protein complexes containing HP1γ in ESCs and compared the profile to that in partially reprogrammed intermediates called pre-iPSCs. Given the differential distribution of the HP1 family in ESCs, we also compared the protein interactome of HP1γ in ESCs with that of HP1α and HP1β. In addition, we probed histone associations of HP1γ in ESCs further by querying the histone post-translational modifications that were detectable. The HP1 proteins themselves are decorated with multiple PTMs, several of which we have found to be novel. Taken together our results reveal the complex contribution of the HP1 proteins to pluripotency.

2017-12-13 | PXD006817 | Pride

Expression data from human bladder cancer cell line with control or knock down of HP1γ (CBX3)

Project description:Cancer development is complicated, it invloves a series of gene expression change. As demonstrated in several reports, HP1γ is upregulated in some types of cancer, and it is essential for cancer development.We want to further clarify HP1γ function in bladder cancer. We used microarrays to determine the gene expression profile in bladder cancer cell line T24 with depletion of HP1γ.

2020-02-20 | GSE95400 | GEO

HP1γ is required for G9a/GLP coactivator function with the glucocorticoid receptor in Nalm6 cells

Project description:Using a genome-wide analysis, we demonstrated that HP1γ is selectively required for GC-regulated expression of GR target genes that require G9a and GLP, consistent with our previous finding that automethylated G9a and GLP recruit HP1g to specific genomic GR binding sites.

2018-10-18 | GSE117796 | GEO

Characterization of histone modifications in mouse embryonic stem cells under control conditions or Phf5a knockdown

Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed for genome-wide localization of H3K4me3, H3K79me2 and H3K36me3 in mouse ESCs under conditions of shControl and shPhf5a knockdown. These results revealed that downregualtion of Phf5a results in the decrease of the elongation marks H3K79me2 and H3K36me3 from the gene bodies of pluripotency genes in ESC, wherease the promoter-associated mark H3K4me3 remains unaffected.

2016-08-31 | GSE73442 | GEO

Knockdown of HP1γ in H1792 cells

Project description:Knockdown of HP1γ in H1792 cells

| PRJNA436586 | ENA

Effect of L-Proline on mouse embryonic stem cells (ESCs)

Project description:We found that the non-essential amino acid L-proline (L-Pro) acts as a signaling molecule that promotes the conversion of embryonic stem cells (ESCs) into mesenchymal-like, spindle-shaped, highly motile, invasive pluripotent stem cells.This embryonic stem cell-to-mesenchymal-like transition (esMT) is accompanied by a genome-wide remodeling of the H3K9me3 and H3K36me3 histone marks. Examination of 2 different histone modifications in untreated ESCs and L-Pro treated ESCs

2013-08-31 | E-GEOD-50477 | biostudies-arrayexpress

SMARCAD1 and TOPBP1 contribute to heterochromatin maintenance at the transition from the 2C-like to the pluripotent state

Project description:Chromocenters are established after the 2-cell (2C) stage during mouse embryonic development, but the factors that mediate chromocenter formation remain largely unknown. To identify regulators of 2C heterochromatin establishment, we generated an inducible system to convert embryonic stem cells (ESCs) to 2C-like cells. This conversion is marked by a global reorganization and dispersion of H3K9me3-heterochromatin foci, which are then reversibly formed upon re-entry into pluripotency. Profiling the chromatin-bound proteome (chromatome) by genome capture of ESCs transitioning to 2C-like cells, we uncover chromatin regulators involved in de novo heterochromatin formation. We identified TOPBP1 and investigated its binding partner SMARCAD1. SMARCAD1 and TOPBP1 associate with H3K9me3-heterochromatin in ESCs. Interestingly, the nuclear localization of SMARCAD1 is lost in 2C-like cells. SMARCAD1 or TOPBP1 depletion in mouse embryos lead to developmental arrest, reduction of H3K9me3 and remodeling of heterochromatin foci. Collectively, our findings contribute to comprehending the maintenance of chromocenters during early development.

2023-04-18 | PXD019703 | Pride

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