Identification of m7G regulator-mediated RNA methylation modification patterns and related immune microenvironment regulation characteristics in heart failure

Abstract

Background

N⁷-methylguanosine (m⁷G) modification has been reported to regulate RNA expression in multiple pathophysiological processes. However, little is known about its role and association with immune microenvironment in heart failure (HF).

Results

One hundred twenty-four HF patients and 135 nonfailing donors (NFDs) from six microarray datasets in the gene expression omnibus (GEO) database were included to evaluate the expression profiles of m⁷G regulators. Results revealed that 14 m⁷G regulators were differentially expressed in heart tissues from HF patients and NFDs. Furthermore, a five-gene m⁷G regulator diagnostic signature, NUDT16, NUDT4, CYFIP1, LARP1, and DCP2, which can easily distinguish HF patients and NFDs, was established by cross-combination of three machine learning methods, including best subset regression, regularization techniques, and random forest algorithm. The diagnostic value of five-gene m⁷G regulator signature was further validated in human samples through quantitative reverse-transcription polymerase chain reaction (qRT-PCR). In addition, consensus clustering algorithms were used to categorize HF patients into distinct molecular subtypes. We identified two distinct m⁷G subtypes of HF with unique m⁷G modification pattern, functional enrichment, and immune characteristics. Additionally, two gene subgroups based on m⁷G subtype-related genes were further discovered. Single-sample gene-set enrichment analysis (ssGSEA) was utilized to assess the alterations of immune microenvironment. Finally, utilizing protein–protein interaction network and weighted gene co-expression network analysis (WGCNA), we identified UQCRC1, NDUFB6, and NDUFA13 as m⁷G methylation-associated hub genes with significant clinical relevance to cardiac functions.

Conclusions

Our study discovered for the first time that m⁷G RNA modification and immune microenvironment are closely correlated in HF development. A five-gene m⁷G regulator diagnostic signature for HF (NUDT16, NUDT4, CYFIP1, LARP1, and DCP2) and three m⁷G methylation-associated hub genes (UQCRC1, NDUFB6, and NDUFA13) were identified, providing new insights into the underlying mechanisms and effective treatments of HF.