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Xist Repeats A and B account for two distinct phases of X-inactivation establishment

ABSTRACT: X-chromosome inactivation (XCI) is a global silencing mechanism by which XX and XY mammals equalize X-linked gene dosages. XCI begins with an establishment phase during which Xist RNA spreads and induces de novo heterochromatinization across a female X chromosome, and is followed by a maintenance phase when multiple epigenetic pathways lock down the inactive X (Xi) state. Involvement of Polycomb repressive complexes 1 and 2 in XCI has been intensively studied, but with conflicting conclusions regarding their recruitment and role in Xi silencing. Here we reveal that establishment of XCI has two phases and reconcile the roles that Xist Repeats A and B play in gene silencing and Polycomb recruitment. Repeat A initiates both processes, whereas Repeat B bolsters or stabilizes them thereafter. Once established, XCI no longer requires Repeat A during maintenance. These findings integrate disparate studies and present a unified view of Xist?s role in Polycomb-mediated silencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE135389 | GEO | 2020/06/15

REPOSITORIES: GEO

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SPEN is required for Xist upregulation during initiation of X chromosome inactivation (ChIP-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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2013-11-04 | E-GEOD-48649 | biostudies-arrayexpress

High-resolution chromosomal maps of Xist RNA reveal a two-step spreading mechanism during X-inactivation

2013-11-04 | GSE48649 | GEO

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Project description:During development, transcriptional and chromatin modification changes co-occur but the order and causality of events often remain unclear. We explore the interrelationship of these processes using the paradigm of X-chromosome inactivation (XCI). We initiate XCI in female, mouse embryonic stem cells by inducing Xist expression and monitor changes in transcription and chromatin by allele-specific TT-seq and ChIP-seq respectively. An unprecedented temporal resolution enabled identification of the earliest chromatin alterations during XCI. We demonstrate that HDAC3 interacts with both NCOR1 and NCOR2 and is pre-bound on the X chromosome where it deacetylates histones to promote efficient gene silencing. We also reveal the choreography of polycomb accumulation following Xist RNA coating, with PRC1-associated H2AK119Ub preceding PRC2-associated H3K27me3. Furthermore, polycomb-associated marks accumulate initially at large, intergenic domains and then spreads into genes but only in the context of gene silencing. Our results provide the hierarchy of chromatin events during XCI and demonstrate that some chromatin changes play key roles in mediating transcriptional silencing.

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Copy number variant (CNV) and Single nucleotide polymorphism (SNP) of UCLA hESC lines

Project description:Female human ESC-lines can carry active X-chromosomes (Xa) or an XIST-RNA- coated inactive X-chromosome (Xi XIST+ ). Additionally, many ESC-lines have abnormal X-chromosome-inactivation (XCI)-states where the Xi no longer expresses XIST-RNA and has transcriptionally active regions (eroded Xi=Xe). The fate of each XCI-state upon differentiation is unclear because individual lines often contain a mixture of XCI-states. Here, we established homogeneous XiXa, XeXa, and XaXa ESC-lines. We found that these lines were unable to initiate XIST-expression and X-chromosome- wide silencing upon differentiation indicating that the ESC XCI-state is maintained in differentiated cells. Consequently, differentiated XeXa and XaXa cells displayed higher levels of X-linked gene-expression than XiXa cells. Although global transcriptional compensation between X-chromosomes and autosomes is not required for female ESC-differentiation, the degree of X-chromosome- silencing influences differentiation efficiencies. Our data suggest that the Xi XIST+ Xa state is inherent to human ESCs and that all other XCI-states, including XaXa, are abnormal and arise during ESC-derivation or maintenance.

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