Date of this Version
Genes & Development
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.
© 2015 Sen et al.; Published by Cold Spring Harbor Laboratory Press.
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aging, epigenetics, H3K36 methylation, cryptic transcription
Sen, P., Dang, W., Donahue, G., Dai, J., Liu, W., Cao, K., Perry, R., Lee, J. Y., Wasko, B. M., Carr, D. T., He, C., Robison, B., Wagner, J., Gregory, B. D., Kaeberlein, M., Kennedy, B. K., Boeke, J. D., & Berger, S. L. (2015). H3K36 Methylation Promotes Longevity by Enhancing Transcriptional Fidelity. Genes & Development, 29 (13), 1362-1376. http://dx.doi.org/10.1101/gad.263707.115
Additional FilesFigure S1_H3K36.pdf (359 kB)
Figure S2_H3K36.pdf (313 kB)
Figure S3_H3K36.pdf (251 kB)
Figure S4_H3K36.pdf (134 kB)
Figure S5_H3K36.pdf (202 kB)
Figure S6_H3K36.pdf (727 kB)
Figure S7_H3K36.pdf (382 kB)
Figure S8_H3K36.pdf (177 kB)
Figure S9_H3K36.pdf (104 kB)
Figure S10_H3K36.pdf (285 kB)
Figure S11_H3K36.pdf (3171 kB)
244 Cryptic Genes in All Experiments_H3K36.xlsx (12 kB)
SuppMaterial_H3K36.pdf (233 kB)
Date Posted: 14 July 2017
This document has been peer reviewed.