S-adenosyl- l -homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling

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.

Functional and Pathological Roles of AHCY

“…Hence, the local recruitment of AHCY seems required to sustain effective transmethylation reactions in time and space. We and others have found that AHCY is recruited to chromatin at specific sites (Aranda et al, 2019;Greco et al, 2020). Our recent discoveries unveil a novel chromatin function of AHCY in controlling gene expression, which is in line with recent data identifying the association of other metabolic enzymes with chromatin (Li et al, 2018).…”

“…Arginines and lysines can be extensively methylated on histone proteins, with the histone 3 lysines 4, 9, 27, 36, and 79 (H3K4, H3K9, H3K27, H3K36, and H3K79, respectively) being the most well-characterized (Zhao and Garcia, 2015). Among the different potential effects of AHCY blockade over histone methylation, the global and local diand tri-methylation of lysine 4 on histone H3 (H3K4me2/3) appears the most sensitive (Fustin et al, 2013;Greco et al, 2020;Zhu et al, 2020). Recently, Greco et al (2020) found that the oscillatory increase of H3K4me3 in circadian rhythmrelated genes is compromised after pharmacological inhibition of AHCY in mouse embryonic fibroblasts.…”

“…Among the different potential effects of AHCY blockade over histone methylation, the global and local diand tri-methylation of lysine 4 on histone H3 (H3K4me2/3) appears the most sensitive (Fustin et al, 2013;Greco et al, 2020;Zhu et al, 2020). Recently, Greco et al (2020) found that the oscillatory increase of H3K4me3 in circadian rhythmrelated genes is compromised after pharmacological inhibition of AHCY in mouse embryonic fibroblasts. At the molecular level, AHCY interacts with BMAL1, a key circadian transcription factor, and regulates the oscillatory recruitment of BMAL1 to chromatin, thus impacting the amplitude of the transcriptional oscillations of circadian rhythm-related genes (Greco et al, 2020) (Figure 2).…”

“…Recently, Greco et al (2020) found that the oscillatory increase of H3K4me3 in circadian rhythmrelated genes is compromised after pharmacological inhibition of AHCY in mouse embryonic fibroblasts. At the molecular level, AHCY interacts with BMAL1, a key circadian transcription factor, and regulates the oscillatory recruitment of BMAL1 to chromatin, thus impacting the amplitude of the transcriptional oscillations of circadian rhythm-related genes (Greco et al, 2020) (Figure 2). The authors suggest that the dimer AHCY-BMAL1 cooperates with histone methyltransferases for gene activation and that AHCY removes excess of SAH to facilitate local histone methylation demands during the transcription peaks.…”

Excess S-Adenosylmethionine inhibits methylation via catabolism to adenine

“…We next tested H3K4Me3, a histone mark that has been shown to contribute to the AHCY-dependent control of cyclic gene expression by the circadian clock and to be inhibited by DZ [46][47][48] . As expected, H3K4Me3 decreased in cells treated for 24h with DZ, adenine, MTA or SAM (Fig.…”