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Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation

ABSTRACT: The Polycomb group proteins are repressive chromatin modifiers with essential roles in metazoan development, cellular differentiation and cell fate maintenance. How Polycomb proteins access active chromatin in order to confer transcriptional silencing during lineage transitions remains unclear. Here we show that the Polycomb Repressive Complex 2 (PRC2) component PHF19 binds the active chromatin mark H3K36me3 via its tudor domain. PHF19 associates with the H3K36me3 demethylase NO66, and is required to recruit the PRC2 complex and NO66 to stem cells genes during differentiation, leading to PRC2 mediated H3K27 tri-methylation, loss of H3K36me3 and transcriptional silencing. We propose a model whereby PHF19 functions during ES cell differentiation to transiently bind the H3K36me3 mark via its tudor domain, forming essential contact points that allow recruitment of PRC2 and H3K36me3 demethylase activity to active gene loci during their transition to a Polycomb-repressed state.

ORGANISM(S): Mus musculus

PROVIDER: GSE41609 | GEO | 2012/11/17

SECONDARY ACCESSION(S): PRJNA177722

REPOSITORIES: GEO

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Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation

Project description:The Polycomb group proteins are repressive chromatin modifiers with essential roles in metazoan development, cellular differentiation and cell fate maintenance. How Polycomb proteins access active chromatin in order to confer transcriptional silencing during lineage transitions remains unclear. Here we show that the Polycomb Repressive Complex 2 (PRC2) component PHF19 binds the active chromatin mark H3K36me3 via its tudor domain. PHF19 associates with the H3K36me3 demethylase NO66, and is required to recruit the PRC2 complex and NO66 to stem cells genes during differentiation, leading to PRC2 mediated H3K27 tri-methylation, loss of H3K36me3 and transcriptional silencing. We propose a model whereby PHF19 functions during ES cell differentiation to transiently bind the H3K36me3 mark via its tudor domain, forming essential contact points that allow recruitment of PRC2 and H3K36me3 demethylase activity to active gene loci during their transition to a Polycomb-repressed state. Examination of PHF19 genome-wide binding in mouse embryonic stem cells

2012-11-17 | E-GEOD-41609 | biostudies-arrayexpress

Phf19 links methylated lysine 36 of histone H3 to regulation of Polycomb activity [ChIP-Seq]

Project description:Polycomb group proteins are transcriptional repressors that play essential roles in regulating genes required for differentiation and embryonic development. The Polycomb repressive complex 2 (PRC2) contains the methyltransferase activity for lysine 27 on histone 3 (H3K27me3), which is a docking site for the PRC1 complex and leads to gene repression. However, the role of other histone modifications in regulating PRC2 activity is just beginning to be understood. Here we show that direct recognition of histone H3 methylated at lysine 36 (H3K36me), an mark associated with activation, by the PRC2 subunit Phf19 is required for the full enzymatic activity of the PRC2 complex. We provide structural evidence for this interaction by nuclear magnetic resonance spectroscopy (NMR). Using genome-wide chromatin binding analyses and expression analyses, we show that Phf19 binds to a subset of PRC2 targets in embryonic stem (ES) cells, and that this is required for their repression and for H3K27me3 deposition. These findings reveal that the H3K36me2/3-Phf19 interaction is essential for PRC2 complex activity and for proper regulation of gene repression in ES cells. We determined the genome binding/occupancy profile of Phf19, H3K36me3, H3K36me2, H3K27me3 and Suz12 by high throughput sequencing in mouse embryonic stem cells. For Phf19 two independent biological replicas were performed and Phf19 binding sites were defined as those sites (ChIP-seq peaks) present in both replicas. H3K27me3 was evaluated in control ES cells and cells depleted of Phf19 (shRd and shPhf19 respectively).

2012-10-16 | E-GEOD-41589 | biostudies-arrayexpress

Phf19 links methylated lysine 36 of histone H3 to regulation of Polycomb activity [ChIP-Seq]

2012-10-16 | GSE41589 | GEO

The Polycomb-Associated Factor Phf19 Controls Hematopoietic Stem Cell Status and Differentiation

Project description:Adult hematopoietic stem cells (HSCs) are rare, multipotent cells in bone marrow that are responsible for generating all blood cell types. HSCs are a heterogeneous group of cells with high plasticity, in part conferred by epigenetic mechanisms. PHF19, a subunit of the Polycomb repressive complex 2 (PRC2), is preferentially expressed in mouse hematopoietic precursors. Here, we show that genetic deletion of Phf19 increases HSC specific status. While proliferation of HSCs is normally triggered by forced mobilization, defects in differentiation impede long-term correct blood production, eventually leading to aberrant hematopoiesis. At the molecular level, PHF19 controls deposition of the histone repressive mark H3K27me3, which accumulates in blood lineage-specific genes. Our results identify PHF19 as having a key role in regulating the epigenetic landscape of HSCs, thus permitting proper blood production.

2020-08-17 | GSE135283 | GEO

Mus musculus

Project description:Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation

| PRJNA177722 | ENA

PHF19 mediated regulation of proliferation and invasiveness in prostate cancer

Project description:The Polycomb-like protein PHF19/PCL3 associates with the Polycomb repressive complex 2 (PRC2) and mediates its recruitment to chromatin in embryonic stem cells, where it is essential for maintaining the repression of developmental genes. PHF19 is also overexpressed in many cancers. However, neither PHF19 targets in cancer cells nor potentially misregulated pathways involving PHF19 are known. Here, we investigate the role of PHF19 in prostate cancer cells. We find that PHF19 interacts with PRC2 and binds to PRC2 targets on chromatin. Direct PHF19 target genes are involved in proliferation, differentiation, angiogenesis, and extracellular matrix organization, among others. Depletion of PHF19 triggers an increase in MTF2/PCL2 recruitment to chromatin, along with a genome-wide gain in PRC2 occupancy and H3K27me3 deposition. Transcriptome analysis shows that loss of PHF19 promotes deregulation of key genes involved in growth, metastasis, and invasion, as well as of factors that stimulate formation of new blood vessels. Consistent with this, PHF19 silencing reduces cell proliferation rate and promotes invasive growth and angiogenesis. Taking together, our findings reveal a role for PHF19 in controlling the balance between cell proliferation and invasiveness in prostate cancer.

2020-03-16 | GSE135623 | GEO

The role of PHF19 in promoting H3K27me3 deposition in multiple myeloma (RNA-Seq)

Project description:Dysregulation of Polycomb Repressive Complex 2 (PRC2) promotes oncogenesis partly through its enzymatic function for inducing tri-methylation of histone H3 lysine 27 (H3K27me3). However, it remains to be determined how PRC2 activity is regulated in normal and diseased settings. We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19, also known as Polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Overexpression and/or genomic amplification of PHF19 is found associated with malignant progression of MM and plasma cell leukemia, correlating to worse treatment outcomes. Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. ChIP-Seq profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains possibly due to impaired H3K27me3 spreading from CpG islands, which is reminiscent to the reported effect of an ‘onco’-histone mutation, H3K27-to-methionine (H3K27M). RNA-Seq-based transcriptome profiling in MM lines also demonstrated a requirement of PHF19 for optimal silencing of PRC2 targets, which include cell cycle inhibitors and interferon-JAK-STAT signaling genes critically involved in tumor suppression.

2019-08-31 | GSE136410 | GEO

ATAC seq data

Project description:Multiple myeloma is associated with an immunosuppressive bone marrow microenvironment instigated and maintained by crosstalk between multiple myeloma cells and the surrounding cells. This crosstalk is facilitated or hindered by epigenetic modifiers altering the gene expression of receptors. The Polycomb-like protein PHF19/PCL3, which mediates polycomb repressive complex 2 (PRC2) recruitment to chromatin, is a high-risk gene whose expression level correlates with poor prognosis in MM patients. Here, we used ATAC seq to define the chromatin accessibility and transcriptional landscape controlling this process by PHF19.

2023-01-31 | GSE224199 | GEO

Mapping polycomb complexes in human and mouse embryonic stem cells

Project description:In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the promoters of more than 2000 genes. To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation followed by ultra high-throughput sequencing. We find that bivalent domains can be segregated into two classes: the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters. We also used computational genomics to search for sequence determinants of Polycomb binding. This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes and underlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes. Keywords: cell type comparison Suz12, Ezh2, Ring1b ChIP-Seq in singlicate from mouse embryonic stem (mES) cells. H3K4me3, H3K27me3, H3K36me3, Ezh2 and Ring1b ChIP-Seq in singlicate from human embyonic stem cells (hES; H9).

2008-11-01 | E-GEOD-13084 | biostudies-arrayexpress

The role of PHF19 in promoting H3K27me3 deposition in multiple myeloma (ChIP-seq)

Project description:We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19, also known as Polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. ChIP-Seq profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains possibly due to impaired H3K27me3 spreading from CpG islands

2019-08-31 | GSE135890 | GEO

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