免疫系统
RNA甲基化
生物
CD8型
甲基化
核糖核酸
细胞生物学
分子生物学
免疫学
基因
生物化学
甲基转移酶
作者
Yanggan Wang,Jian Cheng,Y Wang
摘要
Abstract The latest evidence suggested that the onset of dilated cardiomyopathy (DCM) is closely associated with immune microenvironment disturbance. Since N 6 ‐methyladenosine (m6A) RNA methylation impacts on immunocyte function and antitumor immunity, it is predictable that m6A RNA methylation may result in immune microenvironment disorder. Here, we attempted to verify this hypothesis. We used single‐sample gene set enrichment analysis (ssGSEA) to investigate the infiltration abundance of immunocytes, single‐cell RNA‐Seq to identify key m6A regulator, and a doxorubicin (Dox)‐induced DCM mouse model to confirm our findings. ssGSEA revealed a higher infiltration abundance of CD8 + T lymphocytes, NK cells, monocytes, and B + lymphocytes in DCM myocardium tissue. Single‐cell RNA‐Seq indicated a critical role of IGFBP2 in DCM. Cross‐checking analysis hinted an interaction between IGFBP2 and NSUN5, ALYREF, RRP8, and ALKBH3. Mechanically, IGFBP2‐mediated RNA methylation deteriorated the immune microenvironment and thus increased the risk of DCM by enhancing CD8 + T lymphocyte, NK cell, monocyte, B + lymphocyte infiltration and activating check‐point, MHC‐I, and T cell co‐stimulation signaling pathways. In the DCM mouse model, echocardiography indicated a significant reduction in ejection fraction (EF) and fractional shortening (FS) and an increase in left ventricular internal dimensions at systole (LVIDs) and diastole (LVIDd). MASSON staining indicated an increased fibrosis in myocardium tissue. qPCR and immunofluorescence staining indicated a significant increase in mRNA and protein levels of IGFBP2. The present study indicated that IGFBP2‐mediated RNA methylation remodeled the immune microenvironment and increased the risk of DCM. IGFBP2 may serve as potential therapeutic target for DCM.
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