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Kesner, Barry

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Kesner

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Barry

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Kesner, Barry

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2014 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.eff22e89-85e1-43e2-bb31-427bfc6eca94

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    PAR-TERRA directs homologous sex chromosome pairing
    (2017) Chu, Hsueh-Ping; Froberg, John; Kesner, Barry; Oh, Hyun Jung; Ji, Fei; Sadreyev, Ruslan; Pinter, Stefan F.; Lee, Jeannie
    In mammals, homologous chromosomes rarely pair outside of meiosis. An exception is the X-chromosome, which transiently pairs during X-chromosome inactivation (XCI). How two chromosomes find each other in 3D space is not known. Here, we reveal a required interaction between the X-inactivation center (Xic) and the telomere in mouse embryonic stem cells. The sub-telomeric, pseudoautosomal region (PAR) of both sex chromosomes (X,Y) also undergoes pairing. PAR transcribes a class of telomeric RNA, dubbed “PAR-TERRA”, which accounts for a vast majority of all TERRA transcripts. PAR-TERRA binds throughout the genome, including PAR and Xic. PAR-TERRA anchors the Xic to PAR, creating a “tetrad” of pairwise homologous interactions (Xic:Xic, PAR:PAR, Xic:PAR). Xic pairing occurs within the tetrad. Depleting PAR-TERRA abrogates pairing and blocks initiation of XCI, whereas autosomal PAR-TERRA induces ectopic pairing. We proposed a Constrained Diffusion Model in which PAR-TERRA creates an interaction hub to guide Xic homology searching during XCI.
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    High-resolution Xist binding maps reveal 2-step spreading during X-inactivation
    (2014) Simon, Matthew D.; Pinter, Stefan F.; Fang, Rui; Sarma, Kavitha; Rutenberg-Schoenberg, Michael; Bowman, Sarah K.; Kesner, Barry; Maier, Verena K.; Kingston, Robert; Lee, Jeannie
    The Xist long noncoding RNA (lncRNA) is essential for X-chromosome inactivation (XCI), the process by which mammals compensate for unequal numbers of sex chromosomes1-3. During XCI, Xist coats the future inactive X (Xi)4 and recruits Polycomb Repressive Complex 2 (PRC2) to the X-inactivation center (Xic)5. How Xist spreads silencing on a 150 Mb scale is unclear. Here we generate high-resolution maps of Xist binding on the X chromosome across a developmental time course using CHART-seq. In female cells undergoing XCI de novo, Xist follows a two-step mechanism, initially targeting gene-rich islands before spreading to intervening gene-poor domains. Xist is depleted from genes that escape XCI but may concentrate near escapee boundaries. Xist binding is linearly proportional to PRC2 density and H3 lysine 27 trimethylation (H3K27me3), suggesting co-migration of Xist and PRC2. Interestingly, when the Xi is acutely stripped off Xist in post-XCI cells, Xist recovers quickly within both gene-rich and -poor domains on a time-scale of hours instead of days, suggesting a previously primed Xi chromatin state. We conclude that Xist spreading takes distinct stage-specific forms: During initial establishment, Xist follows a two-step mechanism, but during maintenance, Xist spreads rapidly to both gene-rich and -poor regions.