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Polycomb factor Phf19 controls cell growth and differentiation towards erythroid pathway in chronic myeloid leukemia cells

ABSTRACT: Polycomb group (PcG) of proteins are a group of highly conserved epigenetic regulators involved in many biological functions, such as embryonic development, cell proliferation and adult stem cell determination. PHD finger protein 19 (PHF19) is an associated factor of Polycomb Repressor Complex 2 (PRC2) up-regulated in different human cancers. In particular, myeloid leukemia cell lines show increased levels of PHF19, yet little is known about its function. Here, we have characterized the role of PHF19 in cell lines of a type of myeloid leukemia named chronic myeloid leukemia (CML). Thus, we have demonstrated that PHF19 depletion decreases cell proliferation and promotes differentiation. Mechanistically, we have shown how PHF19 regulates the proliferation of CML through its epigenetic regulation of the cell cycle regulator p21. Furthermore, we have observed that MTF2, a PHF19 homolog, compensates at chromatin level for PHF19 depletion, instructing specific erythroid differentiation. Taken together, our results show that PHF19 is a key transcriptional regulator for cell fate determination and could be a potential target for myeloid leukemia treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164804 | GEO | 2021/04/12

REPOSITORIES: GEO

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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

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

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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

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

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

2012-11-17 | GSE41609 | GEO

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

Polycomb factor Phf19 controls cell growth and differentiation towards erythroid pathway in chronic myeloid leukemia cells

Project description:Polycomb factor Phf19 controls cell growth and differentiation towards erythroid pathway in chronic myeloid leukemia cells

| PRJNA692103 | ENA

Phf19 knockdown effect on F9 embryonal carcinoma cells

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2012-12-20 | E-GEOD-42463 | biostudies-arrayexpress

miR-155 enhances PRC2 activity via polycomb-like protein Phf19 to sustain T cell antitumor immunity [RNA-Seq]

Project description:The microRNA miR-155 is essential for CD8+ T cell antiviral and antitumor immunity but the mechanisms behind its activity remain unresolved. Here, we show that miR-155 increased CD8+ T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of key drivers of effector differentiation. miR-155 enhanced the function of polycomb repressor complex 2 (PRC2) indirectly by promoting the expression of the PRC2 cofactor Phf19 via AKT signaling. Phf19 orchestrated a transcriptional program extensively shared with miR-155 to enhance T cell engraftment, polyfunctionality, and antitumor immunity. These effects were dependent on the histone-binding capacity of Phf19 which is critical for the PRC2 recruitment to chromatin. These findings establish miR-155–Phf19–PRC2 as a pivotal axis regulating CD8+ T cell differentiation. Targeting the microRNA–polycomb-group protein circuitry is a promising route to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate.

2019-03-08 | GSE99801 | GEO

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