Dr. Andrew Duncan contributed to manuscript published in The American Journal of Pathology, entitled, “METTL3 Regulates Liver Homeostasis, Hepatocyte Ploidy, and Circadian Rhythm-Controlled Gene Expression in Mic.”
N6-methyladenosine (m6A), the most abundant internal modification of mRNAs and is installed by METTL3 at the (G/A)(m6A)C motif, plays a critical role in gene expression regulation. METTL3 is essential for embryonic development, and its dysregulation is linked to various diseases. However, the role of METTL3 in liver biology is largely unknown, and, here, METTL3 function was unraveled in mice depleted of Mettl3 in neonatal livers (Mettl3fl/fl; Alb-Cre, “M3LKO”). M3LKO livers exhibited global decrease in m6A on polyadenylated RNAs, and pathological features associated with nonalcoholic fatty liver disease e.g., hepatocyte ballooning, ductular reaction, microsteatosis, pleomorphic nuclei, DNA damage, foci of altered hepatocytes, focal lobular and portal inflammation, and elevated serum ALT/ALP levels. Mettl3-depleted hepatocytes were highly proliferative, with decreased numbers of binucleate hepatocytes and increased nuclear polyploidy. M3LKO livers were characterized by reduced m6A and expression of several key metabolic transcripts regulated by circadian rhythm, and nuclear protein levels of core clock transcription factors, BMAL1 and CLOCK, were also decreased. Significant decrease in total Bmal1 and Clock mRNAs but increase in their nuclear levels were observed in M3LKO livers, suggesting impaired nuclear export. Consistent with the phenotype, meRIP-seq and RNA-seq revealed transcriptome-wide loss of m6A marks and alterations in abundance of mRNAs involved in metabolism in M3LKO. Collectively, METTL3 and m6A modifications are critical regulators of liver homeostasis and function.