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The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis [ChIP-seq]

ABSTRACT: The contribution of epigenetic dysregulation to metastasis remains understudied. Through a meta-analysis of gene expression datasets followed by a mini-screen, we identified PHF8, a histone demethylase of the Jumonji C protein family, as a novel pro-metastatic gene in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro, and increases dissemination but not sub-cutaneous tumor growth in vivo, thus supporting its specific contribution to the acquisition of metastatic potential. PHF8 requires its histone demethylase activity to enhance melanoma cell invasion. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates a molecular program that directly controls the TGFβ signaling pathway and as a consequence, melanoma invasion and metastasis. Our findings bring a mechanistic understanding of epigenetic regulation of metastatic fitness in cancer, which may pave the way for improved therapeutic interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196897 | GEO | 2022/02/23

REPOSITORIES: GEO

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The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis [RNA-seq]

Project description:The contribution of epigenetic dysregulation to metastasis remains understudied. Through a meta-analysis of gene expression datasets followed by a mini-screen, we identified PHF8, a histone demethylase of the Jumonji C protein family, as a novel pro-metastatic gene in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro, and increases dissemination but not sub-cutaneous tumor growth in vivo, thus supporting its specific contribution to the acquisition of metastatic potential. PHF8 requires its histone demethylase activity to enhance melanoma cell invasion. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates a molecular program that directly controls the TGFβ signaling pathway and as a consequence, melanoma invasion and metastasis. Our findings bring a mechanistic understanding of epigenetic regulation of metastatic fitness in cancer, which may pave the way for improved therapeutic interventions.

2022-02-23 | GSE196905 | GEO

The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis

Project description:The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis

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The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis [ChIP-seq]

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PHF8 mediates histone demethylation events in cell cycle progression [expression]

Project description:While reversible histone modifications are linked to an ever-expanding range of biological functions, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here, we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while utilizing multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1/S transition in conjunction with E2F1, HCF-1 and Set1A, at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the Condensin II loading process. Accordingly, the HEAT repeat clusters in two non-SMC Condensin II subunits, N-CAPD3 and N-CAPG2, are capable of recognizing H4K20me1, and ChIP-seq. analysis demonstrate a significant overlap of Condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression. Keywords: Expression profiling by array HeLa cells were transfected with either control or PHF8 siRNAs. Experiments were performed in biological duplicates. RNA were extracted and sujected to microarray analysis.

2010-09-01 | E-GEOD-22477 | biostudies-arrayexpress

PHF8 mediates histone demethylation events in cell cycle progression [ChIP-Seq]

Project description:While reversible histone modifications are linked to an ever-expanding range of biological functions, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here, we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while utilizing multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1/S transition in conjunction with E2F1, HCF-1 and Set1A, at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the Condensin II loading process. Accordingly, the HEAT repeat clusters in two non-SMC Condensin II subunits, N-CAPD3 and N-CAPG2, are capable of recognizing H4K20me1, and ChIP-seq. analysis demonstrate a significant overlap of Condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression. unsynchronized HeLa cells were used to profile H3K4me2 and E2F1; unsynchronized or G1 or G1/S synchronized HeLa cells were used to profile PHF8; M phase synchronized HeLa cells were used to profile SMC4 and H4K20me1

2010-09-01 | E-GEOD-22478 | biostudies-arrayexpress

ChIP-seq experiment of PHF8 in Astrocytes differentiated from mouse NSCs

Project description:In this study we analyzed the contribution of PHF8 histone demethylase to astrocytes differentiation from mouse neural stem cells. We found that PHF8 depletion affects astocytes differentiation. Moreover, PHF8 is crucial for synaptogenesis in neurons/astrocytes cocultures. Genome wide analysis demonstrated that PHF8 controls the expression of critical astrogenic and synaptogenic genes by keeping low levels of H4K20me1 at promoters. PHF8 depletion induces aberrant astrocytes phenotype and caused a significant decrease in miniature excitatory postsynaptic currents (mEPSC) frequency and amplitude in neurons/astrocytes coclutures. These data reveal a new role of PHF8 in astrocyte differentiation and function, modulating neuronal synapse. Thus, lack of histone demethylase activity associated to PHF8 mutations might led to synapse disfunction that could directly impact into X-linked intellectual disabilities.

2021-06-14 | GSE141969 | GEO

PHF8 mediates histone demethylation events in cell cycle progression [ChIP-Seq]

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PHF8 mediates histone demethylation events in cell cycle progression [expression]

2010-09-01 | GSE22477 | GEO

ChIP-seq of PHF8 and H3K4me3

Project description:PHF8 is an H3K9me2 demethylase, interacts with H3K4me3 and RNA Polymerase II, is enriched at thousands of transcription start sites and can act as a transcriptional co-activator. ChIP-seq of PHF8 in HeLa, 293T and Hs68 cells, and of H3K4me3 in Hs68 fibroblasts was performed. Normal IgG-IP or input DNA served as negative controls.

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