Transcriptional regulation of N-6-methyladenosine orchestrates sex-dimorphic metabolic traits
Por:
Salisbury, David A., Casero, David, Zhang, Zhengyi, Wang, Dan, Kim, Jason, Wu, Xiaohui, Vergnes, Laurent, Mirza, Aashiq H., Leon-Mimila, Paola, Williams, Kevin J., Huertas-Vazquez, Adriana, Jaffrey, Samie R., Reue, Karen, Chen, Jianjun, Sallam, Tamer
Publicada:
1 jul 2021
Ahead of Print:
1 jul 2021
Resumen:
Salisbury et al. show that hepatic lipogenic mRNA is regulated by m(6)A
modifications in a sex-dependent and dietary-dependent manner,
contributing to sex-specific differences in hepatic lipid metabolism.
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 N-6-methyladenosine (m(6)A) 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 m(6)A control in male livers
increases hepatic triglyceride stores, leading to a more `feminized'
hepatic lipid composition. Crucially, liver-specific deletion of the
m(6)A complex protein Mettl14 from male and female mice significantly
diminishes sex-specific differences in steatosis. We further surmise
that the m(6)A installing machinery is subject to transcriptional
control by the sex-responsive BCL6-STAT5 axis in response to dietary
conditions. These data show that m(6)A 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.
Filiaciones:
Casero, David:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Zhang, Zhengyi:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Wang, Dan:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Kim, Jason:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Wu, Xiaohui:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Vergnes, Laurent:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Leon-Mimila, Paola:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Huertas-Vazquez, Adriana:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Reue, Karen:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Chen, Jianjun:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
Sallam, Tamer:
Sallam, T (Corresponding Author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA. Sallam, T (Corresponding Author), Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA. Salisbury, David A
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