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RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stablization (ChIP-Seq)

ABSTRACT: Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcription initiation and is essential for maintaining gene silencing at heterochromatic loci. Inhibition of CDK9 increases sensitivity to immunotherapy, but the underlying mechanism remains unclear. We now report that RNF20 stabilizes LSD1 via K29-mediated ubiquitination, which is dependent on CDK9-mediated phosphorylation. This CDK9- and RNF20-dependent LSD1 stabilization is necessary for the demethylation of histone H3K4, then subsequent repression of endogenous retrovirus (ERVs), and an interferon response, leading to epigenetic immunosuppression. Moreover, we found that loss of RNF20 sensitizes cancer cells to the immune checkpoint inhibitor anti-PD-1 in vivo, and that this effect can be rescued by the expression of ectopic LSD1. Our findings are supported by the observation that RNF20 levels correlate with LSD1 levels in human breast cancer specimens. This study sheds light on the role of RNF20 in CDK9-dependent LSD1 stabilization, which is crucial for epigenetic silencing and immunosuppression. Our findings explore the potential importance of targeting the CDK9-RNF20-LSD1 axis in the development of new cancer therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247306 | GEO | 2024/01/18

REPOSITORIES: GEO

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RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stablization (RNA-Seq)

Project description:Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcription initiation and is essential for maintaining gene silencing at heterochromatic loci. Inhibition of CDK9 increases sensitivity to immunotherapy, but the underlying mechanism remains unclear. We now report that RNF20 stabilizes LSD1 via K29-mediated ubiquitination, which is dependent on CDK9-mediated phosphorylation. This CDK9- and RNF20-dependent LSD1 stabilization is necessary for the demethylation of histone H3K4, then subsequent repression of endogenous retrovirus (ERVs), and an interferon response, leading to epigenetic immunosuppression. Moreover, we found that loss of RNF20 sensitizes cancer cells to the immune checkpoint inhibitor anti-PD-1 in vivo, and that this effect can be rescued by the expression of ectopic LSD1. Our findings are supported by the observation that RNF20 levels correlate with LSD1 levels in human breast cancer specimens. This study sheds light on the role of RNF20 in CDK9-dependent LSD1 stabilization, which is crucial for epigenetic silencing and immunosuppression. Our findings explore the potential importance of targeting the CDK9-RNF20-LSD1 axis in the development of new cancer therapies.

2024-01-18 | GSE247307 | GEO

The histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia

Project description:MLL-fusions are potent oncogenes that initiate aggressive forms of acute leukemia. As aberrant transcriptional regulators, MLL-fusion proteins alter gene expression in hematopoietic cells through interactions with the histone H3 lysine 79 (H3K79) methyltransferase DOT1L. Notably, interference with MLL-fusion cofactors like DOT1L is an emerging therapeutic strategy in this disease. Here we identify the histone H2B E3 ubiquitin ligase RNF20 as an additional requirement for MLL-fusion-mediated leukemogenesis. Suppressing the expression of Rnf20 in diverse models of MLL-rearranged leukemia leads to inhibition of cell proliferation; under tissue culture conditions as well as in vivo. Rnf20 knockdown leads to reduced expression of MLL-fusion target genes, including Hoxa9 and Meis1; effects that resemble Dot1l-inhibition. Using ChIP-seq, we found that H2B ubiquitination (H2Bub) is enriched in the body of MLL-fusion target genes, correlating with sites of H3K79 methylation and transcription elongation. Furthermore, we found that Rnf20 is required to maintain local levels of H3K79 di-methylation by Dot1l at Hoxa9 and Meis1. These findings support a model whereby co-transcriptional recruitment of Rnf20 at MLL-fusion target genes leads to amplification of Dot1l-mediated H3K79 methylation, thereby rendering leukemia cells dependent on Rnf20 to maintain their oncogenic transcriptional program. Examination of gene expression profiles upon RNF20 RNAi in MLL-AF9 acute myeloid leukemia cells

2013-02-19 | E-GEOD-43725 | biostudies-arrayexpress

The histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia

2013-02-19 | GSE43725 | GEO

Regulation of gene expression by WAC/RNF20/RNF40 in HEK293A cells

Project description:WAC is a known positive regulator of (macro)autophagy. WAC also forms a complex with RNF20/RNF40 to promote H2B monoubiquitination and hence to affect transcriptional regulation. This study addresses whether the WAC/RNF20/RNF40 complex regulates autophagy through effects on gene expression. WAC, RNF20 and RNF40 were knocked-down using pools of siRNAs in HEK293A cells. Each knockdown was in triplicate and the control was RISCfree siRNA. mRNA expression profiles were investigated using an Illumina HT12v4 Bead Array.

2015-12-17 | E-GEOD-66475 | biostudies-arrayexpress

WT and RNF20 heterozygous-null mice BAT proteome

Project description:Experiments were performed to investigate the BAT proteome of RNF20 WT and heterozygous-null mice.

2024-02-05 | PXD048556 | Pride

Regulation of gene expression by WAC/RNF20/RNF40 in HEK293A cells

2015-12-17 | GSE66475 | GEO

mRNA-seq of intestinal epithelial cells isolated from Rnf20 and Rnf40 knockout mice

Project description:Intestinal epithelial cells (IECs) were isolated from the colon of Villin-CreERT2, Rnf20-flox and Rnf40-flox mice two weeks upon the Tamoxifen-induced, intestinal knockout of Rnf20 and Rnf40. RNA was isolated from snap-frozen IECs to perform mRNA-seq.

2021-06-16 | E-MTAB-9405 | biostudies-arrayexpress

Fbxl19 recruits Rnf20 to CpG Islands and promotes H2B mono-ubiquitination [Affymetrix]

Project description:Rnf20 catalyzes lysine 120 mono-ubiquitination of histone H2B (H2Bub1) that has been previously involved in normal differentiation of embryonic stem (ES) and adult stem cells. However, the mechanisms underlying by which Rnf20 is recruited to its target chromosomal loci to generate H2Bub1 are still elusive. Here, we reveal that Fbxl19, a CxxC domain-containing protein, physically interacts with Rnf20, guides it preferentially to CpG island-containing target promoters, and thereby promotes mono-ubiqutination of H2B. We first show that up-regulation of Fbxl19 induces the level of global H2Bub1, while down-regulation of Fbxl19 reduces the level of H2Bub1 in mouse ES cells. Our genome-wide target mapping unveils the preferential occupancy of Fbxl19 on CpG island-containing promoters, and we further show that the binding of Fbxl19 is essential for the recruitment of Rnf20 to its target genes and subsequent H2Bub1. Altogether, our results demonstrate that Fbxl19 plays critical roles in the H2Bub1 pathway by recruiting Rnf20 to CGI target genes specifically and selectively.

2016-10-01 | GSE76558 | GEO

H3K4me3 occupancy after Rnf20 and Rnf40 knockout in intestinal epithelial cells isolated from mice

Project description:Intestinal epithelial cells (IECs) were isolated from the colon of Villin-CreERT2, Rnf20-flox and Rnf40-flox mice two weeks upon the Tamoxifen-induced, intestinal knockout of Rnf20 and Rnf40. ChIP-seq for H3K4me3 was performed using snap-frozen IECs.

2021-06-16 | E-MTAB-9409 | biostudies-arrayexpress

Fbxl19 recruits Rnf20 to CpG Islands and promotes H2B mono-ubiquitination [ChIP-Seq]

Project description:Rnf20 catalyzes lysine 120 mono-ubiquitination of histone H2B (H2Bub1) that has been previously invloved in normal differentiation of embryonic stem (ES) and adult stem cells. However,the mechanims underlying by which Rnf20 is recruited to its target chromosomal loci to generate H2Bub1 is still elusive. Here, we reveal that Fbxl19, a CxxC domain-containing protein, physically interacts with Rnf20, guides it preferentially to CpG island-containing target promoters, and thereby promotes mono-ubiqutination of H2B. We first show that up-regulation of Fbxl19 induces the level of global H2Bub1, while down-regulation of Fbxl19 reduces the level of H2Bub1 in mouse ES cells. Our genome-wide target mapping unveils the preferential occupancy of Fbxl19 on CpG island-containing promoters, and we further show that the binding of Fbxl19 is essential for the recruitment of Rnf20 to its target genes and subsequent H2Bub1. Altogether, our results demonstrate that Fbxl19 plays critical roles in the H2Bub1 pathway by recruiting Rnf20 to CGI target genes specifically and selectively.

2016-10-01 | GSE76569 | GEO

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