Transcriptional regulation of N(6)-methyladenosine orchestrates sex-dimorphic metabolic traits.
Transcriptional regulation of N(6)-methyladenosine orchestrates sex-dimorphic metabolic traits.
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DOI：
10.1038/s42255-021-00427-2
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发表时间：
2021-07
影响因子：
20.8
通讯作者：
Sallam T
中科院分区：
文献类型：
--
作者：
Salisbury DA;Casero D;Zhang Z;Wang D;Kim J;Wu X;Vergnes L;Mirza AH;Leon-Mimila P;Williams KJ;Huertas-Vazquez A;Jaffrey SR;Reue K;Chen J;Sallam T
男性和女性在代谢特征的患病率方面表现出显著差异，包括肝脂肪变性，这是心脏代谢发病率和死亡率的关键驱动因素。RNA甲基化是一种广泛存在的转录物周转调控机制。在这里，我们表明，存在的RNA修饰N-甲基腺苷（m6 A）分流脂肪生成转录降解和防止肝甘油三酯积累。在雄性而非雌性小鼠中，这种保护性检查点在富含脂质的条件下停滞。雄性肝脏中m6 A控制的丧失增加了肝脏甘油三酯储存，导致肝脏脂质组成更加“女性化”。重要的是，雄性和雌性小鼠的m6 A复合蛋白Mettl 14的肝脏特异性缺失显著减少了脂肪变性的性别特异性差异。我们进一步推测，m6 A安装机器是受转录控制的性别响应BCL 6-STAT 5轴在饮食条件下。这些数据表明，m6 A对于精确和同步控制脂肪生成酶活性是必不可少的，并为肝脏脂质性状中存在性别特异性差异的分子基础提供了见解
Males and females exhibit striking differences in the prevalence of metabolic traits including hepatic steatosis, a key driver of cardiometabolic morbidity and mortality. RNA methylation is a widespread regulatory mechanism of transcript turnover. Here, we show that presence of the RNA modification N⁶-methyladenosine (m6A) triages lipogenic transcripts for degradation and guards against hepatic triglyceride accumulation. In male but not female mice, this protective checkpoint stalls under lipid-rich conditions. Loss of m6A control in male livers increases hepatic triglyceride stores leading to a more “feminized” hepatic lipid composition. Crucially, liver-specific deletion of the m6A complex protein Mettl14 from male and female mice significantly diminishes sex-specific differences in steatosis. We further surmise that m6A installing machinery is subject to transcriptional control by the sex-responsive BCL6-STAT5 axis in response to dietary conditions. These data show that m6A is essential for precise and synchronized control of lipogenic enzyme activity and provide insights into the molecular basis for the existence of sex-specific differences in hepatic lipid traits
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影响因子：
48
作者：
Linder, Bastian;Grozhik, Anya V.;Olarerin-George, Anthony O.;Meydan, Cem;Mason, Christopher E.;Jaffrey, Samie R.
通讯作者：
Jaffrey, Samie R.
影响因子：
30.5
作者：
Casero D;Sandoval S;Seet CS;Scholes J;Zhu Y;Ha VL;Luong A;Parekh C;Crooks GM
通讯作者：
Crooks GM
影响因子：
4.8
作者：
Connerney, Jeannette;Lau-Corona, Dana;Waxman, David J.
通讯作者：
Waxman, David J.
影响因子：
6.5
作者：
Attie, AD;Krauss, RM;Ntambi, JM
通讯作者：
Ntambi, JM
影响因子：
64.8
作者：
Ries, Ryan J.;Zaccara, Sara;Jaffrey, Samie R.
通讯作者：
Jaffrey, Samie R.