Journal Article

SPEN integrates transcriptional and epigenetic control of X-inactivation

Collombet, Samuel, Zhan, Ye, Mercher, Thomas, Żylicz, Jan J., Roensch, Julia, Heard, Edith, Dingli, Florent, Dossin, François, Attia, Mikaël, Dekker, Job, Chelmicki, Tomasz, Kapoor, Varun, Le Saux, Agnès, Pinheiro, Inês, Loew, Damarys

2020

Overview

Xist represents a paradigm for the function of long non-coding RNA in epigenetic regulation, although how it mediates X-chromosome inactivation (XCI) remains largely unexplained. Several proteins that bind to Xist RNA have recently been identified, including the transcriptional repressor SPEN 1 – 3 , the loss of which has been associated with deficient XCI at multiple loci 2 – 6 . Here we show in mice that SPEN is a key orchestrator of XCI in vivo and we elucidate its mechanism of action. We show that SPEN is essential for initiating gene silencing on the X chromosome in preimplantation mouse embryos and in embryonic stem cells. SPEN is dispensable for maintenance of XCI in neural progenitors, although it significantly decreases the expression of genes that escape XCI. We show that SPEN is immediately recruited to the X chromosome upon the upregulation of Xist , and is targeted to enhancers and promoters of active genes. SPEN rapidly disengages from chromatin upon gene silencing, suggesting that active transcription is required to tether SPEN to chromatin. We define the SPOC domain as a major effector of the gene-silencing function of SPEN, and show that tethering SPOC to Xist RNA is sufficient to mediate gene silencing. We identify the protein partners of SPOC, including NCoR/SMRT, the m 6 A RNA methylation machinery, the NuRD complex, RNA polymerase II and factors involved in the regulation of transcription initiation and elongation. We propose that SPEN acts as a molecular integrator for the initiation of XCI, bridging Xist RNA with the transcription machinery—as well as with nucleosome remodellers and histone deacetylases—at active enhancers and promoters. The transcriptional repressor SPEN bridges the non-coding RNA Xist to transcription machinery, histone deacetylases and chromatin remodelling factors to initiate X-chromosome inactivation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/100 / 13/106 / 13/109 / 13/44 / 14/32 / 14/35 / 14/63 / 38/22 / 38/39 / 38/70 / 38/77 / 38/91 / 42/34 / 45/41 / 631/208/200 / 631/337/176/1433 / 631/337/384/2568 / 631/532/2117 / 64/60 / 82/51 / 82/58 / Analysis / Animals / Blastocyst - cytology / Blastocyst - metabolism / Chromatin / Chromatin - genetics / Chromatin - metabolism / Chromosomes / Control / Deactivation / DNA-Binding Proteins - chemistry / DNA-Binding Proteins - metabolism / DNA-directed RNA polymerase / Elongation / Embryo cells / Embryo, Mammalian - cytology / Embryo, Mammalian - metabolism / Embryonic Stem Cells - metabolism / Embryos / Enhancer Elements, Genetic - genetics / Enhancers / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Female / Gene regulation / Gene Silencing / Genes / Genetic transcription / Histone deacetylase / Histone Deacetylases - metabolism / Humanities and Social Sciences / Inactivation / Life Sciences / Male / Methylation / Mice / multidisciplinary / N6-methyladenosine / Neural stem cells / Non-coding RNA / NuRD protein / Promoter Regions, Genetic - genetics / Promoters / Protein Domains / Proteins / Ribonucleic acid / RNA / RNA polymerase / RNA, Long Noncoding - genetics / RNA-Binding Proteins - chemistry / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Stem cell transplantation / Stem cells / Tethering / Transcription elongation / Transcription initiation / Transcription, Genetic / X Chromosome - genetics / X chromosome inactivation / X Chromosome Inactivation - genetics / X chromosomes