Lipopolysaccharide Alters the m6A Epitranscriptomic Tagging of RNAs in Cardiac Tissue.

Ye-Chen Han,Jing-Yi Li,Shu-Yang Zhang,Hong-Zhi Xie,Bo Lu,Hai-Peng Zhang,Ruo-Lan Xiang

doi:10.3389/fmolb.2021.670160

Abstract

N6-methyladenosine (m6A) modification plays important roles in the pathology of a variety of diseases. However, the roles of m6A modification in sepsis-induced myocardial dysfunction are not well defined. Rats were divided into control and lipopolysaccharide (LPS)-induced sepsis group. Global m6A levels of left ventricle tissue were measured by LC-MS/MS, and transcriptome-wide m6A modifications were profiled using epitranscriptomic microarrays (mRNAs and lncRNAs). Bioinformatics analysis was conducted to understand the functional implications of m6A modifications during sepsis. Methylated lncRNAs and mRNAs were measured by m6A single-base site qPCR. The global m6A levels in left ventricle tissue were significantly decreased in the LPS group. While 27 transcripts (23 mRNAs and four lncRNAs) were hypermethylated, 46 transcripts (39 mRNAs and 7 lncRNAs) were hypomethylated in the LPS group. The mRNA expression of writers and readers was significantly decreased in the LPS group. The m6A modification of Clec1b, Stk38l and Tnfrsf26 was associated with platelet activation and apoptotic pathways. Moreover, the decrease in m6A modification of lncRNA XR_346,771 may be related to cation import in cardiac tissue. Our data provide novel information regarding changes to m6A modifications in cardiac tissue during sepsis, and m6A modifications might be promising therapeutic targets.

Highlights

Sepsis is a life-threatening condition involving organ dysfunction that is caused by a dysregulated host response to infection (Cohen et al, 2015), It has been reported that approximately 50% of patients with septic shock are diagnosed with septic cardiomyopathy, which causes myocardial dysfunction, and these patients tend to have poor prognoses (Zaky et al, 2014).Myocardial dysfunction is an important factor that contributes to the high mortality rate of sepsis
The results showed that the m6A modification levels of 62 mRNAs and 11 long non-coding RNAs (lncRNAs) were significantly altered in the LPS group compared with control group (Figures 2A,B)
The results showed that the mRNAs with increased m6A modification levels were enriched in only one pathway, namely, the “PPAR signaling pathway” (Figure 3C)

Summary

Introduction

Sepsis is a life-threatening condition involving organ dysfunction that is caused by a dysregulated host response to infection (Cohen et al, 2015), It has been reported that approximately 50% of patients with septic shock are diagnosed with septic cardiomyopathy, which causes myocardial dysfunction, and these patients tend to have poor prognoses (Zaky et al, 2014). Myocardial dysfunction is an important factor that contributes to the high mortality rate of sepsis. It is necessary to elucidate the pathogenesis of myocardial dysfunction in order to develop new treatment strategies to reduce the mortality rate of sepsis. A series of reversible posttranscriptional modifications located in RNAs have gained increasing attention. More than 140 chemical modifications have been discovered in RNAs. The modifications range from simple methylation or isomerisation, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), pseudouridine (Ψ), 5-methyluridine (m5U),1-methylguanosine, and 7-methylguanosine (m1G and m7G, respectively) and inosine (I), to complex multistep chemical modifications, such as

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