METTL14 Regulates Intestine Cellular Senescence through m6A Modification of Lamin B Receptor

Abstract

N-6-Methyladenosine (m6A) modification is involved in multiple biological processes including aging. However, the regulation of m6A methyltransferase-like 14 (METTL14) in aging remains unclear. Here, we revealed that the level of m6A modification and the expression of METTL14 were particularly decreased in the intestine of aged mice as compared to young mice. Similar results were confirmed in Drosophila melanogaster. Knockdown of Mettl14 in Drosophila resulted in a short lifespan, associated disrupted intestinal integrity, and reduced climbing ability. In human CCD-18Co cells, knockdown of METTL14 accelerated cellular senescence, and the overexpression of METTL14 rescued senescent phenotypes. We also identified the lamin B receptor (LBR) as a target gene for METTL14-mediated m6A modification. Knockdown of METTL14 decreased m6A level of LBR, resulted in LBR mRNA instability, and thus induced cellular senescence. Our findings suggest that METTL14 plays an essential role in the m6A modification-dependent aging process via the regulation of LBR and provides a potential target for cellular senescence.