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E2F1 methylation by SETD6 disrupts BRD4-E2F1 binding and modulates gene regulation in prostate cancer cells

ABSTRACT: The SETD6 protein lysine methyltransferase has a role in the regulation of various cellular processes including cancer initiation and progression. It methylates several cellular proteins including K117 of the E2F1 transcription factor, but the functional consequences of this methylation event are unknown. In this study, the role of SETD6 mediated E2F1 methylation on the progression of prostate cancer was investigated. We identified distinct sets of genes that are bound and upregulated by methylated and unmethylated E2F1. Genes upregulated by methylated E2F1 lead to the negative regulation of cell migration, while genes upregulated by unmethylated E2F1 have roles in cell proliferation and apoptosis. BRD4 is known to bind E2F1 acetylated at K117 and K120. Here, we demonstrate that methylation of E2F1 at K117 prevents E2F1-BRD4 binding of in vitro and in cells establishing the molecular mechanism of the differential gene regulation by methylated and unmethylated E2F1 that depends on SETD6 activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286198 | GEO | 2025/12/22

REPOSITORIES: GEO

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E2F1 methylation by SETD6 disrupts BRD4-E2F1 binding and modulates gene regulation in prostate cancer cells [ChIP-seq]

Project description:The SETD6 protein lysine methyltransferase has a role in the regulation of various cellular processes including cancer initiation and progression. It methylates several cellular proteins including K117 of the E2F1 transcription factor, but the functional consequences of this methylation event are unknown. In this study, the role of SETD6 mediated E2F1 methylation on the progression of prostate cancer was investigated. We identified distinct sets of genes that are bound and upregulated by methylated and unmethylated E2F1. Genes upregulated by methylated E2F1 lead to the negative regulation of cell migration, while genes upregulated by unmethylated E2F1 have roles in cell proliferation and apoptosis. BRD4 is known to bind E2F1 acetylated at K117 and K120. Here, we demonstrate that methylation of E2F1 at K117 prevents E2F1-BRD4 binding of in vitro and in cells establishing the molecular mechanism of the differential gene regulation by methylated and unmethylated E2F1 that depends on SETD6 activity.

2025-12-22 | GSE286020 | GEO

SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [CUT&Run]

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SETD6 Mediates Selective Interaction and Genomic Occupancy of BRD4 and MITF in Melanoma [RNA-seq]

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Project description:Objective: The E2F1 transcription factor regulates the expression of genes involved in cell proliferation, apoptosis and other cellular processes. In addition to regulating transcription, a number of studies have revealed novel, transcription-independent functions for E2F1 in regulating DNA repair. E2F1 localizes to sites of DNA damage dependent on its phosphorylation at serine 31 (serine 29 in mice) by the ATM or ATR kinases. In addition to phosphorylation, E2F1 is also acetylated in response to DNA damage on three lysine residues (K117, K120, and K125 in human E2F1), however how acetylation regulates the DNA repair function of E2F1 is unknown. To study the functional significance of E2F1 acetylation in DNA repair in vivo, we generated a targeted mutant mouse line in which the three sites of E2F1 acetylation were mutated from lysine to arginine and named this allele E2f1 3KR. RNA-seq analysis was performed on wild type and E2f1 3KR mouse embryonic fibroblasts (MEFs), before and after treatment with the radiomimetic drug neocarzinostatin (NCS), to examine the impact of the 3KR mutation on global gene expression patterns.

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Methylation of the transcription factor E2F1 by SETD6 regulates SETD6 expression via a positive feedback mechanism.

Project description:The protein lysine methyltransferase SET domain-containing protein 6 (SETD6) has been shown to influence different cellular activities and to be critically involved in the regulation of diverse developmental and pathological processes. However, the upstream signals that regulate the mRNA expression of SETD6 are not known. Bioinformatic analysis revealed that the SETD6 promoter has a binding site for the transcription factor E2F1. Using various experimental approaches, we show that E2F1 binds to the SETD6 promoter and regulates SETD6 mRNA expression. Our further observation that this phenomenon is SETD6 dependent suggested that SETD6 and E2F1 are linked. We next demonstrate that SETD6 monomethylates E2F1 specifically at K117 in vitro and in cells. Finally, we show that E2F1 methylation at K117 positively regulates the expression level of SETD6 mRNA. Depletion of SETD6 or overexpression of E2F1 K117R mutant, which cannot be methylated by SETD6, reverses the effect. Taken together, our data provide evidence for a positive feedback mechanism, which regulates the expression of SETD6 by E2F1 in a SETD6 methylation-dependent manner, and highlight the importance of protein lysine methyltransferases and lysine methylation signaling in the regulation of gene transcription.

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