Relevance of RNA N6-Methyladenosine Regulators for Pulmonary Fibrosis: Implications for Chronic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis

Abstract

N6-methyladenosine (m6A) modification plays a pivotal role in post-transcriptionally regulating gene expression and biological functions. Nonetheless, the roles of m6A modification in the regulation of chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remain unclear. Twenty-two significant m6A regulators were selected from differential gene analysis between the control and treatment groups from the GSE150910 dataset. Five candidate m6A regulators (insulin-like growth factor binding protein 2, insulin-like growth factor binding protein 3, YTH domain-containing protein 1, zinc finger CCCH domain-containing protein 13, and methyltransferase-like 3) were screened by the application of a random forest model and nomogram model to predict risks of pulmonary fibrosis. The consensus clustering method was applied to divide the treatment samples into two groups with different m6A patterns (clusters A and B) based on the 22 m6A regulators. Our study performed principal component analysis to obtain the m6A-related score of the 288 samples to quantify the two m6A patterns. The study reveals that cluster A was linked to T helper cell (Th) 2-type cytokines, while the immune infiltration of Th1 cytokines was higher in cluster B. Our results suggest that m6A cluster A is likely related to pulmonary fibrosis, indicating m6A regulators play notable roles in the occurrence of pulmonary fibrosis. The m6A patterns could be considered as biomarkers to identify CHP and IPF, which will be helpful to develop immunotherapy strategies for pulmonary fibrosis in the future.

5-methyladenosine regulators play a crucial role in development of chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis

“…In our previous study, we demonstrated that two distinct m6A patterns were associated with fibrosis and might distinguish CHP and IPF 38 . Inspired by these findings, we analyzed expression patterns of the major m5C regulators altered in GSE150910 and found that they played a key role in occurrence and development of CHP and IPF.…”

RNA modifications in pulmonary diseases

“…Significant overexpression of m 6 A regulators IGFBP3, IGFBP5, and ALKBH6 characterizes IPF patients, with a positive association between elevated METTL16 levels and ALKBH6, highlighting the pivotal role of m 6 A modification regulators as IPF biomarkers. 173 The analysis of sequencing data from IPF patients in the GEO database highlights METTL3, a regulatory factor involved in m 6 A methylation, as a promising candidate for predicting risk or assessing prognosis in IPF. 174 METTL3-mediated cir-cRNA m 6 A modifications have been confirmed to correlate with SiO 2 -induced lung fibroblast activation and migration, as well as pulmonary fibrosis outcomes.…”