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Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing [CLIP-seq]

ABSTRACT: Xist orchestrates X chromosome inactivation, a process that entails chromosome-wide silencing and remodeling of the 3-dimensional structure of the X chromosome. Yet, it remains unclear whether these changes in nuclear structure are mediated by Xist and whether they are required for silencing. Here we show that Xist directly interacts with the Lamin B Receptor (LBR), an integral component of the nuclear lamina, and that this interaction is required for Xist-mediated silencing. We show that this interaction recruits the inactive X to the nuclear lamina and by doing so enables Xist to spread to actively transcribed genes across the X. Our results demonstrate that lamina recruitment changes the accessibility of DNA thereby enabling Xist, and its silencing proteins, to spread across the X to silence transcription.

ORGANISM(S): Mus musculus

PROVIDER: GSE86250 | GEO | 2016/09/02

SECONDARY ACCESSION(S): PRJNA341274

REPOSITORIES: GEO

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Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing

Project description:Xist orchestrates X chromosome inactivation, a process that entails chromosome-wide silencing and remodeling of the 3-dimensional structure of the X chromosome. Yet, it remains unclear whether these changes in nuclear structure are mediated by Xist and whether they are required for silencing. Here we show that Xist directly interacts with the Lamin B Receptor (LBR), an integral component of the nuclear lamina, and that this interaction is required for Xist-mediated silencing. We show that this interaction recruits the inactive X to the nuclear lamina and by doing so enables Xist to spread to actively transcribed genes across the X. Our results demonstrate that lamina recruitment changes the accessibility of DNA thereby enabling Xist, and its silencing proteins, to spread across the X to silence transcription. We examined the genomic localization of the Xist lncRNA using RNA Antisense Purification (RAP) in male mouse ES cells where the endogenous Xist promoter is replaced by a tet-inducible one (pSM33) containing 1) wild-type Xist (WT), 2) A-repeat deletion Xist (dA), 3) LBR binding site deletion Xist (dLBS), 4) dLBS-Xist rescued with LMNB1 (LMNB1Res), 5) LBR CRISPRi knock down (LBRKD), or 6) SHARP CRISPRi knock down (SHARPKD).

2016-07-24 | E-GEOD-80510 | biostudies-arrayexpress

Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing

2016-07-24 | GSE80510 | GEO

Systematic Analysis of Allelic Silencing Defines the Interplay of Key Pathways in Xist-mediated Chromosome Inactivation

Project description:Xist RNA, the master regulator of X chromosome inactivation, acts in cis to induce chromosome silencing through the stepwise recruitment of factors that modify underlying chromatin structure. Whilst considerable progress has been made towards defining key silencing factors and the elements to which they bind, their relative contribution to silencing different genes, and their relationship with one another is poorly understood. Here we describe a systematic analysis of Xist-mediated allelic silencing in ES cell-based models. We show that Spen, recruited through the Xist A-repeat, plays a central role, being critical for silencing of all except a subset of low expressed genes. Polycomb, recruited through the Xist B/C-repeat, also plays a key role, favouring silencing of genes with pre-existing H3K27me3 chromatin. LBR and the Rbm15-Mettl3/14 m6A-methyltransferase complex, previously proposed to have a central role, make at most a minor contribution to gene silencing. We integrate our findings in a comprehensive model for Xist-mediated chromosome silencing.

2019-06-17 | GSE119602 | GEO

Xist exploits three-dimensional chromosome architecture to spread across the X-chromosome

2013-05-30 | GSE46918 | GEO

Xist exploits three-dimensional chromosome architecture to spread across the X-chromosome

Project description:Many large noncoding RNAs (lncRNAs) regulate chromatin, but the mechanisms by which they localize to genomic targets remain unexplored. Here we investigate the localization mechanisms of Xist during X-chromosome inactivation (XCI), a paradigm of lncRNA-mediated chromatin regulation. During the maintenance of XCI, Xist binds broadly across the X-chromosome. During initiation of XCI, Xist initially transfers to distal regions across the X-chromosome that are not defined by specific sequences. Instead, Xist identifies these regions by exploiting the three-dimensional conformation of the X-chromosome. Xist initially accumulates on the periphery of actively transcribed regions and requires its silencing domain to spread across active regions. This suggests a model where Xist coats the entire X-chromosome by searching in three dimensions, modifying chromosome structure, and spreading to newly accessible locations. We examined the genomic localization of the Xist lncRNA using RNA Antisense Purification (RAP) in multiple cell contexts: 1) differentiated female cells (MLFs); 2) a time-course of Xist localization in male embryonic stem (ES) cells where the endogenous Xist promoter is replaced by a tet-inducible one (pSM33); 3) a time-course of Xist localization in differentiating female ES cells (F1 2-1); and 4) wild-type (delXF6) and A-repeat deletion (delSXC9) Xist transgenes incorporated into the Hprt locus under the control of a tet-inducible promoter.

2013-05-30 | E-GEOD-46918 | biostudies-arrayexpress

Genomic positioning in LBR and Lamin A K562 knockout cells

Project description:To probe the functional consequences of nuclear lamina genome association, we made LMNA, LBR, and double LMNA/LBR K562 knockout lines. We first examined the genome interaction changes with nulcear lamina using LMNB1 DamID seq and further assessed the functional consequences of these changes using RNA-seq and repli-seq.

2024-04-04 | GSE263012 | GEO

Xist spatially amplifies SHARP recruitment to balance chromosome-wide silencing and specificity to the X chromosome [CLAP]

Project description:Although thousands of lncRNAs are encoded in mammalian genomes, their mechanisms of action are largely uncharacterized because they are often expressed at significantly lower levels than their proposed targets. One such lncRNA is Xist, which mediates chromosome-wide gene silencing on one of the two X chromosomes to achieve gene expression balance between males and females. How a limited number of Xist molecules can mediate robust silencing of a significantly larger number of target genes (~1 Xist RNA: 10 gene targets) while maintaining specificity to genes on the X within each cell is unknown. Here, we show that Xist drives non-stoichiometric recruitment of the essential silencing protein SHARP to amplify its abundance across the inactive X, including at regions not directly occupied by Xist. This amplification is achieved through concentration-dependent homotypic assemblies of SHARP on the X and is required for chromosome-wide silencing. We find that expressing Xist at higher levels leads to increased localization at autosomal regions, demonstrating that low levels of Xist are critical for ensuring its specificity to the X chromosome. We show that Xist (through SHARP) acts to suppress production of its own RNA which may act to constrain overall RNA levels and restrict its ability to spread beyond the X. Together, our results demonstrate a spatial amplification mechanism that allows Xist to achieve two essential but countervailing regulatory objectives: specificity to the X and chromosome-wide gene silencing, and suggest a more general mechanism by which other low abundance lncRNAs can balance specificity to, and robust control of, their regulatory targets.

2022-01-21 | GSE192572 | GEO

Xist spatially amplifies SHARP recruitment to balance chromosome-wide silencing and specificity to the X chromosome [RAP-DNA]

2022-01-21 | GSE192573 | GEO

A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation

Project description:The inactive X chromosome (Xi) serves as a model to understand gene silencing on a global scale. Here, we perform identification of direct RNA interacting proteins? (iDRiP) to isolate a comprehensive protein interactome for Xist, an RNA required for Xi silencing. We discover multiple classes of interactors, including cohesins, condensins, topoisomerases, RNA helicases, chromatin remodelers and modifiers, which synergistically repress Xi transcription. Inhibiting two or three interactors destabilizes silencing. While Xist attracts some interactors, it repels architectural factors. Xist evicts cohesins from the Xi and directs an Xi-specific chromosome conformation. Upon deleting Xist, the Xi acquires the cohesin-binding and chromosomal architecture of the active X. Our study unveils many layers of Xi repression and demonstrates a central role for RNA in the topological organization of mammalian chromosomes. The RNA-seq data sets generated in this study provide a resource for examining the effects of knockdowns of various Xist-interacting proteins on gene expression. The ChIP-seq data sets provide a comprehensive set of data examining CTCF and cohesion binding the X-chromosome, and the effects of deleting Xist on CTCF and cohesion binding. The Hi-C data is an allele-specific contact map of the X-chromosome higher-order chromatin structure in mouse. RNA-seq in 3 control and 10 knockdown cell lines. ChIP-seq for CTCF, Rad21 and Smc1a in wild-type fibroblasts and Xist-deletion fibroblasts. Hi-C in wild-type and Xist-deletion fibroblasts.

2015-06-19 | E-GEOD-67516 | biostudies-arrayexpress

Mus musculus

Project description:Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing

| PRJNA319159 | ENA