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 <i>Drosophila melanogaster</i>. Knockdown of Mettl14 in <i>Drosophila</i> 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.