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.

Methylation across the central dogma in health and diseases: new therapeutic strategies

“…The levels of m 6 A modification decrease in mouse intestine as a consequence of aging. 620 Further study demonstrated METTL14-mediated m 6 A methylation is required for intestinal integrity and normal lifespan of Drosophila melanogaster , partly through the downstream target, Lamin B receptor (LBR). 620 Reduced expression of FTO and ensuing elevated m 6 A level occur in the aged mouse ovary, as well as in granulosa cells of the aged human ovary.…”

“… 620 Further study demonstrated METTL14-mediated m 6 A methylation is required for intestinal integrity and normal lifespan of Drosophila melanogaster , partly through the downstream target, Lamin B receptor (LBR). 620 Reduced expression of FTO and ensuing elevated m 6 A level occur in the aged mouse ovary, as well as in granulosa cells of the aged human ovary. 621 , 622 Consequently, the degradation of a key downstream target mRNA, FOS, is interrupted with the help of reader protein IGF2BP2, contributing to ovarian aging.…”

Biomarkers of Aging and Relevant Evaluation Techniques: A Comprehensive Review

“…Lamin B1, a nuclear layer factor down-regulated in senescent cells, is involved in the regulation of subtelomere genes [ 82 ]. The knockdown of METTL14 reduced the m 6 A level of the lamin B receptor, leading to instability of the lamin B receptor mRNA, which in turn leads to cellular senescence [ 83 ].…”

Nurturing gut health: role of m6A RNA methylation in upholding the intestinal barrier

“…Further cellular experiments revealed that reducing METTL14 led to a decrease in m6A modification in lamin B receptor (LBR) mRNA. This instability in LBR mRNA triggered intestinal cellular senescence [ 114 ]. In LPS-stimulated IECs, suppressing the expression of METTL3 resulted in inhibited cell apoptosis, accompanied by a significant reduction in cleaved-caspase3 and cleaved-caspase9 protein levels [ 115 ].…”