m6A-express: uncovering complex and condition-specific m6A regulation of gene expression

Abstract

N 6 -methyladenosine (m 6 A) is the most abundant form of mRNA modification and controls many aspects of RNA metabolism including gene expression. However, the mechanisms by which m 6 A regulates cell- and condition-specific gene expression are still poorly understood, partly due to a lack of tools capable of identifying m 6 A sites that regulate gene expression under different conditions. Here we develop m 6 A-express , the first algorithm for predicting condition-specific m 6 A regulation of gene expression (m 6 A-reg-exp) from limited methylated RNA immunoprecipitation sequencing (MeRIP-seq) data. Comprehensive evaluations of m 6 A-express using simulated and real data demonstrated its high prediction specificity and sensitivity. When only a few MeRIP-seq samples may be available for the cellular or treatment conditions, m 6 A-express is particularly more robust than the log-linear model. Using m 6 A-express , we reported that m 6 A writers, METTL3 and METTL14, competitively regulate the transcriptional processes by mediating m 6 A-reg-exp of different genes in Hela cells. In contrast, METTL3 induces different m 6 A-reg-exp of a distinct group of genes in HepG2 cells to regulate protein functions and stress-related processes. We further uncovered unique m 6 A-reg-exp patterns in human brain and intestine tissues, which are enriched in organ-specific processes. This study demonstrates the effectiveness of m 6 A-express in predicting condition-specific m 6 A-reg-exp and highlights the complex, condition-specific nature of m 6 A-regulation of gene expression.

The biological function of m6A methyltransferase KIAA1429 and its role in human disease

“…Recently, the role of m6A modification abnormalities in diseases has gradually attracted people’s attention. The m6A modification refered to methylation of the N6 position of adenosine base ( Zhang et al, 2021 ), which can regulate the structure, stability, splicing, export, transcription and decay of mRNA, miRNA and lncRNA through methyltransferases, demethylases and m6A binding proteins, and then widely affect the life processes of various organisms ( Tian et al, 2020 ; Song et al, 2021 ). KIAA1429 is a major m6A methyltransferase and the largest protein of the methyltransferase complex ( Yue et al, 2018 ).…”

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

“…We found that the m 6 A modification level exhibited a particular decline in colon tissues of old mice. Zhang et al had previously uncovered a unique m 6 A-regulation-expression pattern in the human brain and intestine tissues and confirmed m 6 A modification and enrichment to be organ-specific processes [ 48 ]. Similarly, as m 6 A regulators, the altered expression of METTL3 and METTL14 has been observed in various diseases and age-related processes where METTL3/14 was observed as progressively and notably declined in human F2S fibroblasts undergoing replicative senescence [ 19 ].…”

N6-methyladenosine-mediated SH3BP5-AS1 upregulation promotes GEM chemoresistance in pancreatic cancer by activating the Wnt signaling pathway

“…ALKBH5/IGF2BP1-mediated m6A modi cation contributed to SH3BP5-AS1 overexpression m6A modi cation has been con rmed to be involved in the regulation of RNA expression [13] . m6A modi cations are placed and removed by methylases and demethylases, respectively.…”