heardlab.bsky.social

biorxiv.orgX-inactivation escapee domains are CTCF-cohesin independent chromatin compartmentsX-chromosome inactivation involves chromosome-wide gene silencing accompanied by extensive chromatin changes, as well the loss of topologically associating domains. Yet discrete regions of the inactiv...

NEW PREPRINT FROM THE LAB IS OUT — DON’T MISS IT! www.biorxiv.org/content/10.6... We asked whether the 3D architecture of the inactive X - and in particular CTCF and cohesin - is what keeps escapee genes active. Spoiler: it isn’t.

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3/ So what does hold these domains together? We found that escapee domains are fine-scale chromatin compartments, driven by the spatial clustering of H3K27ac-enriched active chromatin and defined by transitions between opposing chromatin states.

4/ The inactive X can therefore maintain active domains without CTCF/cohesin-dependent loops. Instead, chromatin state itself provides the organizing principle for X-inactivation escape.

1/ X-inactivation shuts down most genes on one X chromosome, but some genes escape silencing. These escapees cluster into discrete 3D domains on the inactive X (Xi). So we wondered: are these domains maintained by CTCF and cohesin?

2/ We acutely depleted CTCF and RAD21 in neural progenitor cells with established escape profiles. Despite strongly reducing loop extrusion, escapee gene activity and 3D domain organization remained remarkably stable. No spreading of silencing. No collapse of escape domains.

New preprint from the Heard Lab and the Marti-Renom lab! 🧬 We show that X-inactivation escapee domains form distinct chromatin compartments independently of CTCF and cohesin. www.biorxiv.org/content/10.6...

A big congratulations to all the authors @agneseloda.bsky.social @antonia-hauth.bsky.social @encent.bsky.social @heard65.bsky.social @mamartirenom.bsky.social

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This study was made possible by fantastic collaborations within the @heardlab.bsky.social and beyond. Huge thanks and congratulations to everyone who contributed! 🤩🤩🤩🎉🎉🎉🥳🥳🥳 @odomlab.bsky.social @oliverstegle.bsky.social @howardychang.bsky.social @JudithZaugg

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We propose that natural fluctuations in Xist RNA levels - during development, in adult tissues, or disease - tune escapee gene dosage, laying the groundwork to explore Xist as a molecular signature of X-linked gene mis-regulation in health and disease.

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Replying to @agneseloda.bsky.social

Xist-mediated repression of escapees is SPEN-dependent and reshapes Xi 3D organization: TAD-like domains over escapee clusters are lost upon silencing and re-emerged when transcription resumes.

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Replying to @agneseloda.bsky.social

We show that increasing levels of Xist RNA repress escapee genes, well beyond early development, in differentiated, non-dividing cells and in vivo post implantation embryos.