m ⁶ A mRNA modification maintains colonic epithelial cell homeostasis via NF-κB–mediated antiapoptotic pathway

Abstract

Colonic mucosal barrier dysfunction is one of the major causes of inflammatory bowel disease (IBD). However, the mechanisms underlying mucosal barrier dysfunction are poorly understood. N 6 -methyladenosine (m 6 A) mRNA modification is an important modulator of epitranscriptional regulation of gene expression, participating in multiple physiological and pathological processes. However, the function of m 6 A modification in colonic epithelial cells and stem cells is unknown. Here, we show that m 6 A modification is essential for maintaining the homeostatic self-renewal in colonic stem cells. Specific deletion of the methyltransferase 14 ( Mettl14 ) gene in mouse colon resulted in colonic stem cell apoptosis, causing mucosal barrier dysfunction and severe colitis. Mechanistically, we revealed that Mettl14 restricted colonic epithelial cell death by regulating the stability of Nfkbia mRNA and modulating the NF-κB pathway. Our results identified a previously unidentified role for m 6 A modification in colonic epithelial cells and stem cells, suggesting that m 6 A modification may be a potential therapeutic target for IBD.

Lycopene attenuates the inflammation and apoptosis in aristolochic acid nephropathy by targeting the Nrf2 antioxidant system

“…After IkB is degraded by the proteasome, it leads to the release of NF-κB-p65 into the nucleus [ 69 ]. Subsequently p65 enhances NF-κB-related signaling pathway transduction cascades in a cell-specific manner [ 70 ] and ultimately activats the expression of inflammatory factors. The results of this study showed that AAI activated the expression of TNF-α, NF-κB-p65, and inflammatory factors (IL-1, IL-6, IL-1β) and inhibited the expression of IκB in tubular epithelial cells.…”

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

“…An increase in intestinal permeability would allow bacterial components (e.g., LPS) to enter the bloodstream [ 42 ]. Growing evidence indicated that chronic inflammation accelerates senescence, while inflammation deletion delays senescence [ 43 ]. To our knowledge, disruption of the epithelial integrity allowed for enhanced permeability, bacterial translocation, and inflammation leading to inflammaging.…”

Comprehensive Analysis and Functional Characteristics of Differential Expression of N6-Methyladenosine Methylation Modification in the Whole Transcriptome of Rheumatoid Arthritis

“…m6A plays a key molecular role in regulating RNA maturation, localization, translation, and metabolism [ 6 , 24 , 26 , 28 ]. m6A methylation modification plays an important role in maintaining stem cell metabolism [ 29 ], immune homeostasis [ 30 ], tumor immune microenvironment [ 31 ], immune suppression and escape [ 32 ], and other biological regulations. m6A methylation modification can also affect cell differentiation and proliferation by affecting the expression of transcription factors [ 33 , 34 ].…”