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A 5' fragment of Xist can sequester the RNA of adjacent genes on chromatin

ABSTRACT: Xist requires Repeat-A, a protein binding module in its first two kilobases (2kb), to repress transcription. We report that in mouse embryonic stem cells (ESCs), when expressed as a standalone transcript, the first 2kb of Xist (Xist-2kb) represses the expression of adjacent genes not at the transcriptional level, but by sequestering their mRNA on chromatin. Sequestration does not spread beyond adjacent genes, requires the same sequence elements in Repeat-A that full-length Xist requires to repress transcription, and can be induced by lncRNAs whose sequence composition is related to Xist-2kb. We did not detect local sequestration by full-length Xist, but did detect it by mutant forms of Xist with attenuated transcriptional silencing capability. SPEN and RBM15, Repeat-A binding proteins required for Xist-induced transcriptional silencing, also bound Repeat-A in Xist-2kb, but neither protein was necessary for sequestration. Thus, in mouse ESCs, expression of a 5¢ fragment of Xist that contains Repeat-A can repress gene expression by sequestering nearby mRNAs on chromatin, but it does not induce transcriptional silencing. Rather, Xist-induced transcriptional silencing requires synergy between Repeat-A and additional sequence elements in Xist. These results highlight an important gap in our understanding of the mechanisms through which Repeat-A functions within Xist. We discuss how the mechanisms that underpin sequestration may be relevant to the biology of Xist and of other lncRNAs.

ORGANISM(S): Mus musculus

PROVIDER: GSE120197 | GEO | 2019/05/07

REPOSITORIES: GEO

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An Xist-dependent protein assembly mediates Xist localization and gene silencing

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4sU-seq analysis for tethering hnRNPK to Xist lacking of XR-PID

Project description:Xist lacking of XR-PID (B-repeat and part of C-repeat) can't recruit the polycomb during X chromsome inactivation. The majoring of Xist-mediated chromosomal silencing wouldn’t be achieved. We found that hnRNPK was the one of main contributors for binding B-repeat of Xist. When we tethered hnRNPK to Xist which lacks of XR-PID region, the silencing and polycomb recruitment are restored.

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Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation [ATAC-Seq]

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Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation [RNA-Seq]

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Spen links RNA-mediated endogenous retrovirus silencing and X chromosome inactivation [irCLIP-seq]

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Xist Deletional Analysis Reveals an Interdependency between Xist RNA and Polycomb Complexes for Spreading along the Inactive X

Project description:During X-inactivation, Xist RNA spreads along an entire chromosome to establish silencing. However, the mechanism and functional RNA elements involved in spreading remain undefined. By performing a comprehensive endogenous Xist deletion screen, we identify Repeat B as crucial for spreading Xist and maintaining Polycomb repressive complexes 1 and 2 (PRC1/PRC2) along the inactive X (Xi). Unexpectedly, spreading of these three factors is inextricably linked. Deleting Repeat B or its direct binding partner, HNRNPK, compromises recruitment of PRC1 and PRC2. In turn, ablating PRC1 or PRC2 impairs Xist spreading. Therefore, Xist and Polycomb complexes require each other to propagate along the Xi, suggesting a positive feedback mechanism between RNA initiator and protein effectors. Perturbing Xist/Polycomb spreading causes failure of de novo Xi silencing, with partial compensatory downregulation of the active X, and also disrupts topological Xi reconfiguration. Thus, Repeat B is a multifunctional element that integrates interdependent Xist/ Polycomb spreading, silencing, and changes in chromosome architecture.

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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.

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