@article{b906914c5f1949028acdddeda8b4679a,
title = "Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence",
abstract = "S-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate epigenetic states and subsequent gene expression. This metabolism-epigenome link sensitizes chromatin methylation to altered SAM abundance, yet the mechanisms that allow organisms to adapt and protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear mono-methylation of H3 Lys 9 (H3K9) at the expense of broad losses in histone di- and tri-methylation. Under SAM-depleted conditions, H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide evidence for an adaptive response that enables epigenetic persistence to metabolic stress.",
keywords = "SAM, aging, chromatin, epigenetics, histone, metabolism, methionine, methylation, persistence",
author = "Haws, {Spencer A.} and Deyang Yu and Cunqi Ye and Wille, {Coral K.} and Nguyen, {Long C.} and Krautkramer, {Kimberly A.} and Tomasiewicz, {Jay L.} and Yang, {Shany E.} and Miller, {Blake R.} and Liu, {Wallace H.} and Kazuhiko Igarashi and Rupa Sridharan and Tu, {Benjamin P.} and Cryns, {Vincent L.} and Lamming, {Dudley W.} and Denu, {John M.}",
note = "Funding Information: This research was supported in part by grants from the NIH (T32 DK007665 to S.A.H.; T32 DK007665 to K.A.K.; T32 DK007665 and F32 GM128399 to W.H.L.; GM113033 to R.S.; R01 GM094314 to B.P.T.; K99 GM129415 to C.Y.; R37 GM059785 to J.M.D.; and AG041765, AG050135, AG051974, AG056771, and AG062328 to D.W.L.); grants-in-aid from the Japan Society for the Promotion of Science (18H05374 to K.I.); a UW-Madison SCRMC postdoctoral fellowship (C.K.W.); a New Investigator Program Award (D.W.L.) and a Collaborative Health Sciences Program Award (V.L.C.) from the Wisconsin Partnership Program; the V Foundation for Cancer Research (V.L.C.); and a Glenn Foundation Award for Research in the Biological Mechanisms of Aging (D.W.L.) as well as startup funds from the UW-Madison School of Medicine and Public Health and the UW-Madison Department of Medicine (V.L.C. and D.W.L.). This research was conducted while D.W.L. was an AFAR Research Grant recipient from the American Federation for Aging Research. D.Y. was supported in part by a fellowship from the American Heart Association (17PRE33410983). The Lamming laboratory is supported in part by the U.S. Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. This work does not represent the views of the Department of Veterans Affairs or the United States Government. We would like to thank Alexis J. Lawton for the bioinformatics analysis presented in Figure S3I. We would also like to thank the University of Wisconsin-Madison Biotechnology Center and the University of Wisconsin-Madison Center for High Throughput Computing for their help in generating and analyzing the ChIP-sequencing data presented in Figure 5. Conceptualization, S.A.H. D.W.L. V.L.C. and J.M.D.; Methodology, S.A.H. C.Y. C.K.W. L.N.C. W.H.L. K.I. B.P.T. D.W.L. and J.M.D.; Validation, S.A.H. D.Y. C.Y. L.N.C. K.A.K. K.I. B.P.T. D.W.L. and J.M.D.; Formal Analysis, S.A.H. D.Y. C.K.W. K.A.K. D.W.L. and J.M.D; Investigation, S.A.H. D.Y. C.Y. L.N.C. K.A.K. J.L.T. S.E.Y. and B.R.M.; Resources, K.I. B.P.T. V.L.C. D.W.L. and J.M.D.; Writing – Original Draft, S.A.H. and J.M.D.; Writing – Review & Editing, S.A.H. D.Y. C.Y. C.K.W. W.H.L. K.I. R.S. B.P.T. V.L.C. D.W.L. and J.M.D.; Visualization, S.A.H. D.Y. and D.W.L.; Supervision and Project Administration, K.I. R.S. B.P.T. D.W.L. and J.M.D.; Funding Acquisition, S.A.H. C.Y. C.K.W. W.H.L. K.A.K. K.I. R.S. B.P.T. V.L.C. D.W.L. and J.M.D. J.M.D. is a consultant for FORGE Life Sciences and co-founder of Galilei BioSciences. D.W.L has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. The remaining authors declare no competing interests. Funding Information: This research was supported in part by grants from the NIH ( T32 DK007665 to S.A.H.; T32 DK007665 to K.A.K.; T32 DK007665 and F32 GM128399 to W.H.L.; GM113033 to R.S.; R01 GM094314 to B.P.T.; K99 GM129415 to C.Y.; R37 GM059785 to J.M.D.; and AG041765 , AG050135 , AG051974 , AG056771 , and AG062328 to D.W.L.); grants-in-aid from the Japan Society for the Promotion of Science ( 18H05374 to K.I.); a UW-Madison SCRMC postdoctoral fellowship (C.K.W.); a New Investigator Program Award (D.W.L.) and a Collaborative Health Sciences Program Award (V.L.C.) from the Wisconsin Partnership Program ; the V Foundation for Cancer Research (V.L.C.); and a Glenn Foundation Award for Research in the Biological Mechanisms of Aging (D.W.L.) as well as startup funds from the UW-Madison School of Medicine and Public Health and the UW-Madison Department of Medicine (V.L.C. and D.W.L.). This research was conducted while D.W.L. was an AFAR Research Grant recipient from the American Federation for Aging Research . D.Y. was supported in part by a fellowship from the American Heart Association ( 17PRE33410983 ). The Lamming laboratory is supported in part by the U.S. Department of Veterans Affairs ( I01-BX004031 ), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital . This work does not represent the views of the Department of Veterans Affairs or the United States Government. We would like to thank Alexis J. Lawton for the bioinformatics analysis presented in Figure S3 I. We would also like to thank the University of Wisconsin-Madison Biotechnology Center and the University of Wisconsin-Madison Center for High Throughput Computing for their help in generating and analyzing the ChIP-sequencing data presented in Figure 5 . Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = apr,
day = "16",
doi = "10.1016/j.molcel.2020.03.004",
language = "English",
volume = "78",
pages = "210--223.e8",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}