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SETDB1/HUSH modulates Xist RNA levels during establishment of X chromosome inactivation [RNA-Seq]

ABSTRACT: The non-coding RNA Xist mediates X chromosome inactivation (XCI) in mammals, functioning in cis to direct heterochromatin formation over a single X chromosome in cells of early female embryos. Prior studies have determined that Xist transcription and turnover are modulated to maintain the correct level of Xist RNA to inactivate a single X chromosome. The underlying molecular mechanisms are poorly understood. In this study we demonstrate that RNA-dependent recruitment of the H3K9me3 methyltransferase SETDB1 and the HUSH complex across the transcribed Xist locus functions to suppress Xist transcription during establishment of XCI. Thus, degron-mediated acute depletion of SETDB1 or core HUSH subunits abrogates allelic H3K9me3 deposition, increasing Xist transcription, accumulation of Xist RNA, and the rate of X chromosome gene silencing. Our findings support a model in which the SETDB1/HUSH pathway coordinates Xist transcription rates to maintain optimal Xist RNA levels, ensuring the silencing of a single X chromosome.

ORGANISM(S): Mus musculus

PROVIDER: GSE310108 | GEO | 2026/03/12

REPOSITORIES: GEO

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SETDB1/HUSH modulates Xist RNA levels during establishment of X chromosome inactivation [ChIP-Seq]

Project description:The non-coding RNA Xist mediates X chromosome inactivation (XCI) in mammals, functioning in cis to direct heterochromatin formation over a single X chromosome in cells of early female embryos. Prior studies have determined that Xist transcription and turnover are modulated to maintain the correct level of Xist RNA to inactivate a single X chromosome. The underlying molecular mechanisms are poorly understood. In this study we demonstrate that RNA-dependent recruitment of the H3K9me3 methyltransferase SETDB1 and the HUSH complex across the transcribed Xist locus functions to suppress Xist transcription during establishment of XCI. Thus, degron-mediated acute depletion of SETDB1 or core HUSH subunits abrogates allelic H3K9me3 deposition, increasing Xist transcription, accumulation of Xist RNA, and the rate of X chromosome gene silencing. Our findings support a model in which the SETDB1/HUSH pathway coordinates Xist transcription rates to maintain optimal Xist RNA levels, ensuring the silencing of a single X chromosome.

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SETDB1/HUSH modulates Xist RNA levels during establishment of X chromosome inactivation [4sU-seq]

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SPEN is a molecular integrator that bridges Xist with transcriptional and epigenetic control of X-chromosome inactivation

Project description:Xist represents a paradigm for long non-coding RNA function in epigenetic regulation, although how it mediates X-chromosome inactivation (XCI) remains largely unexplained. Multiple Xist-RNA binding proteins have recently been identified, including SPEN/SHARP, whose knockdown has been associated with deficient XCI at multiple loci. Here we demonstrate that SPEN is a key orchestrator of XCI in vivo and unravel its mechanism of action. We show that SPEN is essential for initiating gene silencing on the X chromosome in preimplantation mouse embryos and embryonic stem cells. On the other hand, SPEN is dispensable for maintenance of XCI in neural progenitor cells, although it significantly dampens expression of genes that escape from XCI. During initiation of XCI, we show by live-cell imaging and CUT&RUN approaches that SPEN is immediately recruited to the X chromosome upon Xist up-regulation, where it is targeted to enhancers and promoters of actively transcribed genes. SPEN rapidly disengages from chromatin once silencing is accomplished, implying a need for active transcription to tether it to chromatin. We define SPEN’s SPOC (SPEN paralog and ortholog C-terminal) domain as a major effector of SPEN’s gene silencing function, and show that artificial tethering of SPOC to Xist RNA is sufficient to mediate X-linked gene silencing. We identify SPOC’s protein partners which include NCOR/SMRT, the m6A RNA methylation machinery, the NuRD complex, RNA polymerase II and factors involved in regulation of transcription initiation and elongation. We propose that SPEN acts as a molecular integrator for initiation of XCI, bridging Xist RNA with the transcription machinery as well as nucleosome remodelers and histone deacetylases, at active enhancers and promoters.

2021-04-19 | PXD015699 | Pride

SETDB1/HUSH modulates Xist RNA levels during establishment of X chromosome inactivation

Project description:SETDB1/HUSH modulates Xist RNA levels during establishment of X chromosome inactivation

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SETDB1/HUSH modulates Xist RNA levels during establishment of X chromosome inactivation [RNA-Seq]

Project description:SETDB1/HUSH modulates Xist RNA levels during establishment of X chromosome inactivation [RNA-Seq]

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ZNF638 represses HBV covalently closed circular DNA transcription involving HUSH complex epigenetic silencing

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RNA binding by Periphilin plays an essential role in initiating silencing by the HUSH complex

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