S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling.
S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling.
复制标题
S-腺苷-L-氢绿碱水解酶将蛋氨酸代谢与昼夜节律的时钟和染色质重塑联系在一起。
DOI：
10.1126/sciadv.abc5629
复制
发表时间：
2020-12
期刊：
影响因子：
13.6
通讯作者：
Sassone-Corsi P
中科院分区：
文献类型：
--
作者：
Greco CM;Cervantes M;Fustin JM;Ito K;Ceglia N;Samad M;Shi J;Koronowski KB;Forne I;Ranjit S;Gaucher J;Kinouchi K;Kojima R;Gratton E;Li W;Baldi P;Imhof A;Okamura H;Sassone-Corsi P
S-腺苷高半胱氨酸（SAH）水解酶AHCY在功能上将生物钟与甲硫氨酸代谢联系起来。由转录激活因子CLOCK和BMAL 1驱动的昼夜节律基因表达与动态染色质重塑密切相关。然而，细胞代谢如何指导昼夜染色质重塑实际上是未知的。我们报告，S-腺苷高半胱氨酸（SAH）水解酶腺苷高半胱氨酸酶（AHCY）循环协会时钟BMAL 1在染色质位点，促进昼夜转录活性。SAH是S-腺苷甲硫氨酸（SAM）依赖性甲基转移酶的有效反馈抑制剂，AHCY及时水解SAH对维持甲基化反应至关重要。我们表明，AHCY是必不可少的循环H3 K4三甲基化，全基因组招募BMAL 1染色质，随后的昼夜节律转录。哺乳动物细胞中AHCY的消耗或靶向药理学抑制显著降低昼夜节律基因表达的幅度。在小鼠中，下丘脑中AHCY的药理学抑制改变了昼夜运动活动和视交叉上核内的节律性转录。这些结果揭示了细胞代谢、染色质动力学和昼夜节律调节之间的一种以前未被认识到的联系。
The S-adenosylhomocysteine (SAH) hydrolyzing enzyme AHCY functionally links the circadian clock to methionine metabolism. 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.
登录
查看更多内容
DOI：
10.1073/pnas.1721371115
发表时间：
2018-06-05
影响因子：
11.1
作者：
Fustin JM;Kojima R;Itoh K;Chang HY;Ye S;Zhuang B;Oji A;Gibo S;Narasimamurthy R;Virshup D;Kurosawa G;Doi M;Manabe I;Ishihama Y;Ikawa M;Okamura H
通讯作者：
Okamura H
影响因子：
56.9
作者：
Balsalobre, A;Brown, SA;Schibler, U
通讯作者：
Schibler, U
影响因子：
4.8
作者：
Etchegaray, Jean-Pierre;Yang, Xiaoming;Reppert, Steven M.
通讯作者：
Reppert, Steven M.
影响因子：
64.8
作者：
Dickinson ME;Flenniken AM;Ji X;Teboul L;Wong MD;White JK;Meehan TF;Weninger WJ;Westerberg H;Adissu H;Baker CN;Bower L;Brown JM;Caddle LB;Chiani F;Clary D;Cleak J;Daly MJ;Denegre JM;Doe B;Dolan ME;Edie SM;Fuchs H;Gailus-Durner V;Galli A;Gambadoro A;Gallegos J;Guo S;Horner NR;Hsu CW;Johnson SJ;Kalaga S;Keith LC;Lanoue L;Lawson TN;Lek M;Mark M;Marschall S;Mason J;McElwee ML;Newbigging S;Nutter LM;Peterson KA;Ramirez-Solis R;Rowland DJ;Ryder E;Samocha KE;Seavitt JR;Selloum M;Szoke-Kovacs Z;Tamura M;Trainor AG;Tudose I;Wakana S;Warren J;Wendling O;West DB;Wong L;Yoshiki A;International Mouse Phenotyping Consortium;Jackson Laboratory;Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS);Charles River Laboratories;MRC Harwell;Toronto Centre for Phenogenomics;Wellcome Trust Sanger Institute;RIKEN BioResource Center;MacArthur DG;Tocchini-Valentini GP;Gao X;Flicek P;Bradley A;Skarnes WC;Justice MJ;Parkinson HE;Moore M;Wells S;Braun RE;Svenson KL;de Angelis MH;Herault Y;Mohun T;Mallon AM;Henkelman RM;Brown SD;Adams DJ;Lloyd KC;McKerlie C;Beaudet AL;Bućan M;Murray SA
通讯作者：
Murray SA
影响因子：
64.5
作者：
Chang HC;Guarente L
通讯作者：
Guarente L