期刊
SCIENCE ADVANCES
卷 6, 期 51, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abc5629
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资金
- National Cancer Institute of the NIH [T32CA009054]
- European Union [749869]
- NIH F31 Kirschstein-NRSA Predoctoral Fellowship [F31GM117942]
- American Heart Association Predoctoral Fellowship [17PRE33410952]
- NIH [GM123558, P50 GM076516, P41GM103540, R21DK114652, R21AG053592]
- CREST Japan Science and Technology Agency [JPMJCR14W3]
- Novo Nordisk Foundation [NNF-202585]
- Japan Society for the Promotion of Science (JSPS)
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [325871075-SFB 1309]
- Marie Curie Actions (MSCA) [749869] Funding Source: Marie Curie Actions (MSCA)
- UKRI [MR/S031812/1] Funding Source: UKRI
Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.
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