Integrative network-based analysis on multiple Gene Expression Omnibus datasets identifies novel immune molecular markers implicated in non-alcoholic steatohepatitis

Jun-Jie Zhang; Yan Shen; Xiao-Yuan Chen; Man-Lei Jiang; Feng-Hua Yuan; Shui-Lian Xie; Jie Zhang; Fei Xu

doi:10.3389/fendo.2023.1115890

Integrative network-based analysis on multiple Gene Expression Omnibus datasets identifies novel immune molecular markers implicated in non-alcoholic steatohepatitis

Front Endocrinol (Lausanne). 2023 Mar 16:14:1115890. doi: 10.3389/fendo.2023.1115890. eCollection 2023.

Authors

Jun-Jie Zhang¹, Yan Shen², Xiao-Yuan Chen², Man-Lei Jiang³, Feng-Hua Yuan¹, Shui-Lian Xie¹, Jie Zhang³, Fei Xu³

Affiliations

¹ Center for Molecular Pathology, Department of Basic Medicine, Gannan Medical University, Ganzhou, China.
² Department of Publication Health and Health Management, Gannan Medical University, Ganzhou, China.
³ Department of Hepatology, The Affiliated Fifth People's Hospital of Ganzhou, Gannan Medical University, Ganzhou, China.

Abstract

Introduction: Non-alcoholic steatohepatitis (NASH), an advanced subtype of non-alcoholic fatty liver disease (NAFLD), has becoming the most important aetiology for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. This study were designed to explore novel genes associated with NASH.

Methods: Here, five independent Gene Expression Omnibus (GEO) datasets were combined into a single cohort and analyzed using network biology approaches.

Results: 11 modules identified by weighted gene co-expression network analysis (WGCNA) showed significant association with the status of NASH. Further characterization of four gene modules of interest demonstrated that molecular pathology of NASH involves the upregulation of hub genes related to immune response, cholesterol and lipid metabolic process, extracellular matrix organization, and the downregulation of hub genes related to cellular amino acid catabolic, respectively. After DEGs enrichment analysis and module preservation analysis, the Turquoise module associated with immune response displayed a remarkably correlation with NASH status. Hub genes with high degree of connectivity in the module, including CD53, LCP1, LAPTM5, NCKAP1L, C3AR1, PLEK, FCER1G, HLA-DRA and SRGN were further verified in clinical samples and mouse model of NASH. Moreover, single-cell RNA-seq analysis showed that those key genes were expressed by distinct immune cells such as microphages, natural killer, dendritic, T and B cells. Finally, the potential transcription factors of Turquoise module were characterized, including NFKB1, STAT3, RFX5, ILF3, ELF1, SPI1, ETS1 and CEBPA, the expression of which increased with NASH progression.

Discussion: In conclusion, our integrative analysis will contribute to the understanding of NASH and may enable the development of potential biomarkers for NASH therapy.

Keywords: hub genes; immune response; non-alcoholic steatohepatitis; transcription factors; weighted gene co-expression network analysis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biomarkers / metabolism
Computational Biology
Gene Expression
Immediate-Early Proteins* / genetics
Liver Neoplasms* / genetics
Membrane Proteins / genetics
Mice
Non-alcoholic Fatty Liver Disease* / metabolism

Substances

Biomarkers
Laptm5 protein, mouse
Membrane Proteins
Immediate-Early Proteins

Grants and funding

This research was funded by the National Natural Science Foundation of China (82200653), the doctoral startup fund of Gannan Medical University (QD202112).