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Two H3K23 histone methyltransferases, SET-32 and SET-21, function synergistically to promote nuclear RNAi-mediated transgenerational epigenetic inheritance in Caenorhabditis elegans

ABSTRACT: Nuclear RNAi in C. elegans induces a set of transgenerationally heritable marks of H3K9me3, H3K23me3, and H3K27me3 at the target genes. The function of H3K23me3 in the nuclear RNAi pathway is largely unknown due to the limited knowledge of H3K23 histone methyltransferase (HMT). In this study we identified SET-21 as a novel H3K23 HMT. By taking combined genetic, biochemical, and genomic approaches we found that SET-21 functions synergistically with a previously reported H3K23 HMT SET-32 to deposit H3K23me3 at the native targets of germline nuclear RNAi. We identified a subset of nuclear RNAi targets that became transcriptionally activated in the set-21;set-32 double mutant. SET-21 and SET-32 are also required for a robust transgenerational gene silencing induced by exogenous dsRNA. The set-21;set-32 double mutant exhibited an enhanced mortal germline phenotype at a high temperature compared to the set-32 single mutant. Together, these results support a model in which H3K23 HMTs SET-21 and SET-32 function cooperatively to ensure the robustness of germline nuclear RNAi and promotes the germline immortality under the heat stress.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Simone Sidoli

LAB HEAD: Simone Sidoli

PROVIDER: PXD052034 | Pride | 2024-12-06

REPOSITORIES: Pride

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			Action	DRS
	20230512_Laura_Sam_A1.msf	Msf
	20230512_Laura_Sam_A1.raw	Raw
	20230512_Laura_Sam_A2.raw	Raw
	20230512_Laura_Sam_A3.raw	Raw
	20230512_Laura_Sam_B1.raw	Raw

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Two H3K23 histone methyltransferases, SET-32 and SET-21, function synergistically to promote germline nuclear RNAi, proper endogenous siRNA expression, and germline immortality in Caenorhabditis elegans [RNA-seq]

Project description:Nuclear RNAi in C. elegans induces a set of transgenerationally heritable marks of H3K9me3, H3K23me3, and H3K27me3 at the target genes. The function of H3K23me3 in the nuclear RNAi pathway is largely unknown due to the limited knowledge of H3K23 histone methyltransferase (HMT). In this study we identified SET-21 as a novel H3K23 HMT. By taking combined genetic, biochemical, and genomic approaches we found that SET-21 functions synergistically with a previously reported H3K23 HMT SET-32 to deposit H3K23me3 at the native targets of germline nuclear RNAi. We identified a subset of nuclear RNAi targets become transcriptionally activated in the set-21;set-32 double mutant. SET-21 and SET-32 are also required for a robust transgenerational gene silencing induced by exogenous dsRNA. The loss of SET-21 and SET-32 leads to a mortal germline phenotype, similar to mutations of the core nuclear RNAi component. Together, these results support a model in which H3K23 HMTs SET-21 and SET-32 ensure the robustness of germline nuclear RNAi and promotes the germline immortality at a high temperature.

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Histone ubiquitination-methylation crosstalk involving UHRF1 and SUV39H1/2 reinforces heterochromatin states in response to DNA hypomethylation

Project description:Histone H3 mono-ubiquitination, catalyzed by the RING E3 ubiquitin ligase UHRF1, is appreciated as a docking site for DNMT1 during DNA replication to facilitate DNA methylation maintenance. Its functions beyond this are unknown. Here, we identify simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/2-dependent H3K9me3 as prominent epigenetic alterations accompanying DNA hypomethylation induced by DNMT1 inhibition. Integrative epigenomics analyses reveal that transient accumulation of hemi-methylated DNA, resulting from incomplete DNA methylation maintenance, stimulates UHRF1-dependent H3K18ub at CpG islands that nucleates new domains of H3K9me3 and impedes PRC2 activity in these genomic regions. Notably, H3K18ub enhances the methyltransferase activity of SUV39H1/2, leading to increased H3K9me3 at these CpG island promoters. Blocking H3K18ub-dependent SUV39H1/2 activity enhances the efficacy of DNMT1 inhibitors. Collectively, these findings reveal a novel histone ubiquitination-methylation crosstalk mechanism that reinforces heterochromatin states in the absence of DNA methylation and proposes new strategies for improving cancer epigenetic therapy.

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A truncated and catalytically inactive form of KDM5B histone demethylase accumulates in breast cancer cells and regulates H3K4 tri-methylation and gene expression

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Decoupling the downstream effects of germline nuclear RNAi reveals that transcriptional repression and heritable RNAi are independent of the H3K9me3 response in C. elegans [ChIP-seq]

Project description:Germline nuclear RNAi in C. elegans is a transgenerational gene-silencing pathway that leads to the H3K9 trimethylation (H3K9me3) response and transcriptional repression of target genes. The H3K9me3 response induced either by exogenous dsRNA or endogenous siRNA (endo-siRNA) is highly specific to the target loci and transgenerationally heritable. Despite these features, the role of H3K9me3 in transcriptional repression and heritable gene silencing at native target genes has not been tested. To resolve this gap, we first determined that the combined activities of three H3K9 histone methyltransferases (HMTs), MET-2, SET-25, and SET-32, are responsible for virtually all of the detectable level of germline nuclear RNAi-dependent H3K9me3 at native genes, triggered either by exogenous dsRNA or endo-siRNAs. By performing RNA Polymerase II ChIP-seq and pre-mRNA-seq analyses, we found that the loss of the H3K9me3 response at germline nuclear RNAi targets in the met-2;set-25;set-32 mutant does not lead to any defect in transcriptional repression or heritable RNAi. Therefore, H3K9me3 is not required for exogenous dsRNA-induced heritable RNAi or the maintenance of endo siRNA-mediated transcriptional silencing in C. elegans germline. This study provides a unique paradigm in which transcriptional silencing and heterochromatin, triggered by the same upstream pathway, can be decoupled.

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Decoupling the downstream effects of germline nuclear RNAi reveals that transcriptional repression and heritable RNAi are independent of the H3K9me3 response in C. elegans [pre-mRNA-seq]

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Decoupling the downstream effects of germline nuclear RNAi reveals that transcriptional repression and heritable RNAi are independent of the H3K9me3 response in C. elegans [RNA-seq]

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C. elegans nuclear RNAi factor SET-32 is an H3K23 methyltransferase and deposits the transgenerational heritable modification of H3K23me3

Project description:Nuclear RNAi provides a highly tractable system to study RNA-mediated chromatin changes and epigenetic inheritance. Recent studies indicate that nuclear RNAi-mediated heterochromatin is highly complex in its regulation and function. The knowledge of histone modifications that are involved in nuclear RNAi and the corresponding histone modifying enzymes remains limited. In this study, we show that the heterochromatin mark H3K23me3 is induced by nuclear RNAi at both exogenous and endogenous targets in C. elegans. In addition, RNAi-induced H3K23me3 can be inherited for at least four generations. We also demonstrate that the histone methyltransferase SET-32, methylates H3K23 in vitro. Both set-32 and the germline nuclear RNAi Argonaute, hrde-1, are required for nuclear RNAi-induced H3K23me3 in vivo. Our data poise H3K23me3 as a chromatin modification involved in the nuclear RNAi pathway and provides the field with a new target for uncovering the role of heterochromatin in transgenerational epigenetic silencing.

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