title: Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism.
abstract: S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) link one-carbon metabolism to methylation status. However, it is unknown whether regulation of SAM and SAH by nutrient availability can be directly sensed to alter the kinetics of key histone methylation marks. We provide evidence that the status of methionine metabolism is sufficient to determine levels of histone methylation by modulating SAM and SAH. This dynamic interaction led to rapid changes in H3K4me3, altered gene transcription, provided feedback regulation to one-carbon metabolism, and could be fully recovered upon restoration of methionine. Modulation of methionine in diet led to changes in metabolism and histone methylation in the liver. In humans, methionine variability in fasting serum was commensurate with concentrations needed for these dynamics and could be partly explained by diet. Together these findings demonstrate that flux through methionine metabolism and the sensing of methionine availability may allow direct communication to the chromatin state in cells.
authors.affiliation: Department of Molecular Biology and Genetics, Field of Biochemistry, Molecular, and Cell Biology, Cornell University, Ithaca, NY 14853, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Mentch
authors.affiliation: Department of Molecular Biology and Genetics, Field of Genomics, Genetics and Development, Cornell University, Ithaca, NY 14853, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Mahya
authors.initials: M
authors.lastname: Mehrmohamadi
authors.affiliation: Department of Biological Statistics and Computational Biology, Field of Computational Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Diwakar
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Orentreich Foundation for the Advancement of Science, Cold Spring, NY 10516, USA.
authors.forename: Dwight
authors.initials: D
authors.lastname: Mattocks
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Gómez Padilla
authors.affiliation: Orentreich Foundation for the Advancement of Science, Cold Spring, NY 10516, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Ables
authors.affiliation: UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Marcas M
authors.initials: MM
authors.lastname: Bamman
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Thalacker-Mercer
authors.affiliation: Orentreich Foundation for the Advancement of Science, Cold Spring, NY 10516, USA.
authors.forename: Sailendra N
authors.initials: SN
authors.lastname: Nichenametla
authors.affiliation: Department of Molecular Biology and Genetics, Field of Biochemistry, Molecular, and Cell Biology, Cornell University, Ithaca, NY 14853, USA; Department of Molecular Biology and Genetics, Field of Genomics, Genetics and Development, Cornell University, Ithaca, NY 14853, USA; Department of Biological Statistics and Computational Biology, Field of Computational Biology, Cornell University, Ithaca, NY 14853, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: jason.locasale@duke.edu.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
mesh_terms: D000818:Animals; D002244:Carbon / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008715:Methionine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D019875:One-Carbon Group Transferases / Q000235:genetics / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D002244:Carbon; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D019875:One-Carbon Group Transferases; D011495:Histone-Lysine N-Methyltransferase
keywords: chromatin biology; epigenetics; metabolomics; one carbon metabolism