Satellite repeat transcripts modulate heterochromatin condensates and safeguard chromosome stability in mouse embryonic stem cells

Clara Lopes Novo (), Emily V. Wong, Colin Hockings, Chetan Poudel, Eleanor Sheekey, Meike Wiese, Hanneke Okkenhaug, Simon J. Boulton, Srinjan Basu, Simon Walker, Gabriele S. Kaminski Schierle, Geeta J. Narlikar and Peter J. Rugg-Gunn ()
Additional contact information
Clara Lopes Novo: The Babraham Institute
Emily V. Wong: University of California San Francisco
Colin Hockings: University of Cambridge
Chetan Poudel: University of Cambridge
Eleanor Sheekey: The Babraham Institute
Meike Wiese: University of Cambridge
Hanneke Okkenhaug: The Babraham Institute
Simon J. Boulton: The Francis Crick Institute
Srinjan Basu: University of Cambridge
Simon Walker: The Babraham Institute
Gabriele S. Kaminski Schierle: University of Cambridge
Geeta J. Narlikar: University of California San Francisco
Peter J. Rugg-Gunn: The Babraham Institute

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Heterochromatin maintains genome integrity and function, and is organised into distinct nuclear domains. Some of these domains are proposed to form by phase separation through the accumulation of HP1ɑ. Mouse heterochromatin contains noncoding major satellite repeats (MSR), which are highly transcribed in mouse embryonic stem cells (ESCs). Here, we report that MSR transcripts can drive the formation of HP1ɑ droplets in vitro, and modulate heterochromatin into dynamic condensates in ESCs, contributing to the formation of large nuclear domains that are characteristic of pluripotent cells. Depleting MSR transcripts causes heterochromatin to transition into a more compact and static state. Unexpectedly, changing heterochromatin’s biophysical properties has severe consequences for ESCs, including chromosome instability and mitotic defects. These findings uncover an essential role for MSR transcripts in modulating the organisation and properties of heterochromatin to preserve genome stability. They also provide insights into the processes that could regulate phase separation and the functional consequences of disrupting the properties of heterochromatin condensates.

Date: 2022
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DOI: 10.1038/s41467-022-31198-3

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