Genomewide Histone H3 Lysine 9 Acetylation Profiling in CD4+ T Cells Revealed Endoplasmic Reticulum Stress Deficiency in Patients with Acute-on-chronic Liver Failure.

Abstract

Acute-on-chronic liver failure (ACLF) displayed 'sepsis-like' immune paralysis. Little is known about the role of CD4+ T lymphocytes, the primary regulator of innate and adopted immune system, played in ACLF. Acetylation of histone H3 lysine 9 (H3K9ac), a key epigenetic modification, tightly controls gene transcription. Whether and how does H3K9ac modification regulate CD4+ T cells in ACLF remains unclear. PBMCs were isolated from patients with ACLF, immune tolerance of chronic hepatitis B (CHB-T) and immune active of chronic hepatitis B (CHB-A). Then, CD4+ T lymphocytes were purified by magnetic microbeads, and the purity was confirmed by flow cytometry. H3K9ac variations were analysed in CD4+ T cells using chromatin immunoprecipitation microarray and then confirmed by quantitative PCR. Whole-genome H3K9 acetylation analyses were conducted by bioinformatics. A total of 70 genes were differently modified in H3K9ac between CHB-A and ACLF groups, while 44 genes were differently modified in H3K9ac between CHB-T and ACLF groups. Clustering algorithm analysis showed patients with ACLF displayed 'sepsis-like' immune paralysis. Functional analysis showed endoplasmic reticulum (ER) stress, or downstream pathway-related genes, such as BIP, ATF4, PER1, CSNK1D, IRF3, BNIP1, AKT1 and UBC, were differentially modified in ACLF. We profiled H3K9 acetyl modification in CD4+ T lymphocytes from HBV-infected patients with three different immune states, that is ACLF, immune tolerance and immune active phases. ACLF displayed 'sepsis-like' immune paralysis. ER stress in CD4+ T lymphocytes attributed to ACLF. This study provides some useful clues for revealing the mechanisms underlying ACLF.