Noncoding RNA-nucleated heterochromatin spreading is intrinsically labile and requires accessory elements for epigenetic stability.

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Abstract

The heterochromatin spreading reaction is a central contributor to the formation of gene-repressive structures, which are re-established with high positional precision, or fidelity, following replication. How the spreading reaction contributes to this fidelity is not clear. To resolve the origins of stable inheritance of repression, we probed the intrinsic character of spreading events in fission yeast using a system that quantitatively describes the spreading reaction in live single cells. We show that spreading triggered by noncoding RNA-nucleated elements is stochastic, multimodal, and fluctuates dynamically across time. This lack of stability correlates with high histone turnover. At the mating type locus, this unstable behavior is restrained by an accessory cis-acting element REIII, which represses histone turnover. Further, REIII safeguards epigenetic memory against environmental perturbations. Our results suggest that the most prevalent type of spreading, driven by noncoding RNA-nucleators, is epigenetically unstable and requires collaboration with accessory elements to achieve high fidelity.

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All data generated or analysed during this study are included in the manuscript and supporting files. The code for analyzing live cell data is included in the submission. All reagents generated in this work are available upon request.

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R A Greenstein

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Stephen K Jones

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
Eric C Spivey

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4080-8616
James R Rybarski

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
Ilya J Finkelstein

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9371-2431
Bassem Al-Sady

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, United States

For correspondence
bassem.al-sady@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8996-7941

Funding

National Institutes of Health (DP2GM123484)

Bassem Al-Sady

Program for Breakthrough Biomedical Research, University of California, San Francisco (New Frontier Research)

Bassem Al-Sady

American Federation of Aging Research (AFAR-020)

Ilya J Finkelstein

National Institutes of Health (F32 AG053051)

Stephen K Jones

Welch Foundation (F-l808)

Ilya J Finkelstein

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.