H3K36 methylation promotes longevity by enhancing transcriptional fidelity
- Payel Sen1,9,
- Weiwei Dang1,2,9,
- Greg Donahue1,
- Junbiao Dai3,8,
- Jean Dorsey1,
- Xiaohua Cao2,
- Wei Liu3,
- Kajia Cao1,
- Rocco Perry1,
- Jun Yeop Lee4,
- Brian M. Wasko5,
- Daniel T. Carr5,
- Chong He6,
- Brett Robison6,
- John Wagner4,
- Brian D. Gregory4,
- Matt Kaeberlein5,
- Brian K. Kennedy6,
- Jef D. Boeke3,7 and
- Shelley L. Berger1
- 1Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 2Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA;
- 3High-Throughput Biology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
- 4Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 5Department of Pathology, University of Washington, Seattle, Washington 98195, USA;
- 6The Buck Institute of Research on Aging, Novato, California 94945, USA;
- 7Institute for Systems Genetics, New York University Langone Medical Center, New York, New York 10016, USA
- Corresponding authors: bergers{at}upenn.edu, weiwei.dang{at}bcm.edu
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↵9 These authors contributed equally to this work.
Abstract
Epigenetic mechanisms, including histone post-translational modifications, control longevity in diverse organisms. Relatedly, loss of proper transcriptional regulation on a global scale is an emerging phenomenon of shortened life span, but the specific mechanisms linking these observations remain to be uncovered. Here, we describe a life span screen in Saccharomyces cerevisiae that is designed to identify amino acid residues of histones that regulate yeast replicative aging. Our results reveal that lack of sustained histone H3K36 methylation is commensurate with increased cryptic transcription in a subset of genes in old cells and with shorter life span. In contrast, deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes, suppresses cryptic transcript initiation, and extends life span. We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to life span, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.263707.115.
- Received April 11, 2015.
- Accepted June 16, 2015.
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