Transcriptional regulation of N6-methyladenosine orchestrates sex-dimorphic metabolic traits

Abstract

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

Integrative analysis reveals multiple modes of LXR transcriptional regulation in liver

“…To understand how changes in transcription in the absence of LXRs related to genome-wide chromatin accessibility, we performed ATAC-Seq to quantify genome-wide chromatin accessibility on the livers of the same mice used in the transcriptomics analysis above. It has been reported that changes in accessibility in response to perturbation in the liver are less dramatic than in other tissues ( 15 , 35 , 36 ). A total of 95,342 peaks were detected across the samples.…”

Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex

“…To further investigate this, we used a state-of-the-art mass spectrometry approach to assess the impact of PRV or HSV-1 infection on the levels of m6A in mRNA in infected cells. The method relies on the specific digestion of m6A in the DRACH (in which D can be A, G, or U; R can be A and G; and H can be A, C, or U) context, which eliminates m6A signal from rRNA ( Salisbury et al, 2021 ; Mirza et al, 2022 ). Figures 1A and 1B show that both alphaherpesviruses trigger a dramatic decrease in m6A-methylated mRNA.…”

“…To specifically quantify m6A levels in mRNA, a sequential digestion protocol was used to only free m6A in the GAC context ( Salisbury et al, 2021 ; Mirza et al, 2022 ). m6A in contaminating rRNA is not present in the GAC consensus sequence and is thus not digested.…”

N6-methyladenosine modification governs liver glycogenesis by stabilizing the glycogen synthase 2 mRNA

“…In addition, m6A modi cation can also orchestrate sex-dimorphic metabolic traits in liver. Loss of m6A control in male livers increases hepatic triglyceride stores, leading to a more 'feminized' hepatic lipid composition 33 . All the evidence supports that dynamic modi cation of m6A is essential for the multiple functions of liver tissues.…”