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RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stablization

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247308 | GEO | 2024/01/18

REPOSITORIES: GEO

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RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stabilization.

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, 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.

| S-EPMC10873621 | biostudies-literature

RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stablization (ChIP-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 | GSE247306 | GEO

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

RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stablization

Project description:RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stablization

| PRJNA1037084 | ENA

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

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

| PRJNA1037089 | ENA

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

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

| PRJNA1037090 | ENA

RNF20 controls astrocytic differentiation through epigenetic regulation of STAT3 in the developing brain.

Project description:Astrocyte has crucial roles in the central nervous system and accumulating evidence has shown its core function for brain complexity, plasticity and cognition. However, the essential key factors in the precise regulation of astrocytic differentiation remain largely uncharacterized. Here, we identified that RNF20, an E3 ligase of H2BK120 in the mammalian system, regulates astrocyte production from neural precursor cells. RNF20 deficiency by shRNA knockdown or deletion in conditional knockout mice impairs the astrocytic differentiation. Overexpression of RNF20 promotes astrocytic differentiation and can rescue the astrocyte production deficiency caused by RNF20 disruption. Furthermore, we demonstrate that RNF20 functions cooperatively with acetyltransferase MOF to promote astrocytic generation. RNF20-mediated H2Bub1 cooperating with MOF-mediated H4K16ac activates the transcription of Stat3. Together, these data indicate RNF20 is a critical regulator of astrocytic production, which may contribute to the understanding of neurological disorders with glial dysgenesis.

| S-EPMC5762844 | biostudies-literature

A C. elegans LSD1 demethylase contributes to germline immortality by reprogramming epigenetic memory.

Project description:Epigenetic information undergoes extensive reprogramming in the germline between generations. This reprogramming may be essential to establish a developmental ground state in the zygote. We show that mutants in spr-5, the Caenorhabditis elegans ortholog of the H3K4me2 demethylase LSD1/KDM1, exhibit progressive sterility over many generations. This sterility correlates with the misregulation of spermatogenesis-expressed genes and transgenerational accumulation of the histone modification dimethylation of histone H3 on lysine 4 (H3K4me2). This suggests that H3K4me2 can serve as a stable epigenetic memory, and that erasure of H3K4me2 by LSD/KDM1 in the germline prevents the inappropriate transmission of this epigenetic memory from one generation to the next. Thus, our results provide direct mechanistic insights into the processes that are required for epigenetic reprogramming between generations.

| S-EPMC2672044 | biostudies-literature

Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression.

Project description:The available evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity is largely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viral oncogene homolog (MYC) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocyte lineage transcription factor 2 (OLIG2), SRY (sex determining region Y)-box 2 (SOX2), and POU class 3 homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development.

| S-EPMC4522819 | biostudies-literature

CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-07-24 | GSE189130 | GEO