S-adenosyl-l-homocysteine Hydrolase Links Methionine Metabolism to the Circadian Clock and Chromatin Remodeling

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2020 Dec 17

PMID 33328229

Citations 31

Authors

Carolina Magdalen Greco

Marlene Cervantes

Jean-Michel Fustin

Kakeru Ito

Nicholas Ceglia

Muntaha Samad

Jiejun Shi

Kevin Brian Koronowski

Ignasi Forne

Suman Ranjit

Jonathan Gaucher

Kenichiro Kinouchi

Rika Kojima

Enrico Gratton

Wei Li

Pierre Baldi

Axel Imhof

Hitoshi Okamura

Paolo Sassone-Corsi

Affiliations

Soon will be listed here.

Abstract

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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