S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
30
04
2020
accepted:
30
10
2020
entrez:
17
12
2020
pubmed:
18
12
2020
medline:
16
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33328229
pii: 6/51/eabc5629
doi: 10.1126/sciadv.abc5629
pmc: PMC7744083
pii:
doi:
Substances chimiques
ARNTL Transcription Factors
0
Bmal1 protein, mouse
0
Chromatin
0
S-Adenosylhomocysteine
979-92-0
Methionine
AE28F7PNPL
CLOCK Proteins
EC 2.3.1.48
Clock protein, mouse
EC 2.3.1.48
Adenosylhomocysteinase
EC 3.3.1.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : F31 GM117942
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009054
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG053592
Pays : United States
Organisme : NIDDK NIH HHS
ID : R21 DK114652
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM076516
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103540
Pays : United States
Organisme : Medical Research Council
ID : MR/S031812/1
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM123558
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK121425
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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