The role of PHF19 in promoting H3K27me3 deposition in multiple myeloma (ChIP-seq)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE135890 | GEO | 2019/08/31
REPOSITORIES: GEO
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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
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
Project description:To determine the effect of overexpression PHF19 in ARP1 myeloma cells Drug resistance is a major reason for the recurrence of multiple myeloma (MM). In addition to genetic mutations, epigenetic abnormalities are involved in the whole process of MM relapse and drug resistance. In this study, we investigate the roles of polycomb like protein 19 (PHF19), a critical gene involved in the epigenetic regulation of gene expression, in the development of MM. The gene expression profiling (GEP) data shows that PHF19 is significantly up-regulated in MM cells and associated with shortened progression-free survival and overall survival in MM patients. PHF19 promotes MM cell growth both in vitro and in a subcutaneous xenograft mouse model. Up-regulated PHF19 is also associated with the development of resistance to multiple drugs, including bortezomib, in MM cells. Moreover, miR-15a can directly target PHF19 by binding to its 3'-UTR. Since miR-15a is down-regulated in MM cells, PHF19 is considered to be up-regulated due to loss of the suppression by miR-15a. The mechanistic investigations indicate that PHF19 can activate AKT which in turn leads to an increase in the phosphorylation of EZH2, a core component of PRC2 that mediates the histone H3K27 methylation. Subsequently suppresses histone H3K27 methylation and causes up-regulated expression of several anti-apoptotic genes, including BCL-xL, MCL-1 and HIF-1alpha. Moreover, PDK1 activation is significantly increased in PHF19 overexpressing MM cells.
2020-03-31 | GSE128406 | GEO
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
Project description:PCL family protein Phf19/Pcl3 is one of the accessory components of the PRC2 core complex, and Phf19 is highly expressed in murine ES cells and an ES cell-like embryonic carcinoma cell line, F9 cells. Here we performed microarray analysis of embryonal carcinoma cell line F9 following Phf19 knockdown by shRNA. Knocking down Phf19/Pcl3 in F9 embryonic cells led to derepression of numerous PRC2 direct target genes. 4 sampels including 2 shRNA vector control cell lines and 2 shPhf19 cell lines were used for RNA extraction and Affymetrix mouse 430 2.0 arrays.
2012-12-20 | E-GEOD-42463 | biostudies-arrayexpress
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.
2012-10-16 | GSE41589 | GEO
Project description:PCL family protein Phf19/Pcl3 is one of the accessory components of the PRC2 core complex, and Phf19 is highly expressed in murine ES cells and an ES cell-like embryonic carcinoma cell line, F9 cells. Here we performed microarray analysis of embryonal carcinoma cell line F9 following Phf19 knockdown by shRNA. Knocking down Phf19/Pcl3 in F9 embryonic cells led to derepression of numerous PRC2 direct target genes.
2012-12-20 | GSE42463 | GEO
Project description: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.
2021-04-12 | GSE164804 | GEO
Project description:T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here, we show that miR-155 increased CD8+ T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhanced Polycomb Repressor Complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2 associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrated a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8+ T cell antitumor responses. These effects relied on Phf19 histone-binding capacity, which is critical for PRC2 recruitment to chromatin. These findings establish the miR-155–Phf19–PRC2 as a pivotal axis regulating CD8+ T cell differentiation, paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate.
2019-03-29 | GSE128664 | GEO
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