Dataset Information

BAZ2A-RNA mediated association with TOP2A and KDM1A represses genes implicated in prostate cancer.

ABSTRACT: BAZ2A represses rRNA genes (rDNA) that are transcribed by RNA polymerase I. In prostate cancer (PCa), BAZ2A function goes beyond this role because it represses genes frequently silenced in metastatic disease. However, the mechanisms of this BAZ2A-mediated repression remain elusive. Here, we show that BAZ2A represses genes through its RNA-binding TAM domain using mechanisms differing from rDNA silencing. Although the TAM domain mediates BAZ2A recruitment to rDNA, in PCa, this is not required for BAZ2A association with target genes. Instead, the BAZ2A-TAM domain in association with RNA mediates the interaction with topoisomerase 2A (TOP2A) and histone demethylase KDM1A, whose expression positively correlates with BAZ2A levels in localized and metastatic PCa. TOP2A and KDM1A pharmacological inhibition up-regulate BAZ2A-repressed genes that are regulated by inactive enhancers bound by BAZ2A, whereas rRNA genes are not affected. Our findings showed a novel RNA-based mechanism of gene regulation in PCa. Furthermore, we determined that RNA-mediated interactions between BAZ2A and TOP2A and KDM1A repress genes critical to PCa and may prove to be useful to stratify prostate cancer risk and treatment in patients.

SUBMITTER: Roganowicz M

PROVIDER: S-EPMC10130768 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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BAZ2A-RNA mediated association with TOP2A and KDM1A represses genes implicated in prostate cancer.

Roganowicz Marcin M Bär Dominik D Bersaglieri Cristiana C Aprigliano Rossana R Santoro Raffaella R

Life science alliance 20230425 7

BAZ2A represses rRNA genes (rDNA) that are transcribed by RNA polymerase I. In prostate cancer (PCa), BAZ2A function goes beyond this role because it represses genes frequently silenced in metastatic disease. However, the mechanisms of this BAZ2A-mediated repression remain elusive. Here, we show that BAZ2A represses genes through its RNA-binding TAM domain using mechanisms differing from rDNA silencing. Although the TAM domain mediates BAZ2A recruitment to rDNA, in PCa, this is not required for ...[more]

PMID: 37184661

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Project description:RNA interference (RNAi) refers to the ability of exogenously introduced double-stranded RNA to silence expression of homologous sequences. Silencing is initiated when the enzyme Dicer processes the double-stranded RNA into small interfering RNAs (siRNAs). Small RNA molecules are incorporated into Argonaute-protein-containing effector complexes, which they guide to complementary targets to mediate different types of gene silencing, specifically post-transcriptional gene silencing and chromatin-dependent gene silencing. Although endogenous small RNAs have crucial roles in chromatin-mediated processes across kingdoms, efforts to initiate chromatin modifications in trans by using siRNAs have been inherently difficult to achieve in all eukaryotic cells. Using fission yeast, here we show that RNAi-directed heterochromatin formation is negatively controlled by the highly conserved RNA polymerase-associated factor 1 complex (Paf1C). Temporary expression of a synthetic hairpin RNA in Paf1C mutants triggers stable heterochromatin formation at homologous loci, effectively silencing genes in trans. This repressed state is propagated across generations by the continual production of secondary siRNAs, independently of the synthetic hairpin RNA. Our data support a model in which Paf1C prevents targeting of nascent transcripts by the siRNA-containing RNA-induced transcriptional silencing complex and thereby epigenetic gene silencing, by promoting efficient transcription termination and rapid release of the RNA from the site of transcription. We show that although compromised transcription termination is sufficient to initiate the formation of bi-stable heterochromatin by trans-acting siRNAs, impairment of both transcription termination and nascent transcript release is imperative to confer stability to the repressed state. Our work uncovers a novel mechanism for small-RNA-mediated epigenome regulation and highlights fundamental roles for Paf1C and the RNAi machinery in building epigenetic memory.

Dataset Information

BAZ2A-RNA mediated association with TOP2A and KDM1A represses genes implicated in prostate cancer.

Publications

BAZ2A-RNA mediated association with TOP2A and KDM1A represses genes implicated in prostate cancer.

Similar Datasets

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