Abstract
Clonal hematopoiesis of indeterminate potential (CHIP), a common aging-related process that predisposes individuals to various inflammatory responses, has been reported to be associated with COVID-19 severity. However, the immunological signature and the exact gene expression program by which the presence of CHIP exerts its clinical impact on COVID-19 remain to be elucidated. In this study, we generated a single-cell transcriptome landscape of severe COVID-19 according to the presence of CHIP using peripheral blood mononuclear cells. Patients with CHIP exhibited a potent IFN-γ response in exacerbating inflammation, particularly in classical monocytes, compared to patients without CHIP. To dissect the regulatory mechanism of CHIP (+)-specific IFN-γ response gene expression in severe COVID-19, we identified DNMT3A CHIP mutation-dependent differentially methylated regions (DMRs) and annotated their putative target genes based on long-range chromatin interactions. We revealed that CHIP mutant-driven hypo-DMRs at poised cis-regulatory elements appear to facilitate the CHIP (+)-specific IFN-γ-mediated inflammatory immune response. Our results highlight that the presence of CHIP may increase the susceptibility to hyperinflammation through the reorganization of chromatin architecture, establishing a novel subgroup of severe COVID-19 patients.
【초록키워드】 COVID-19, Transcriptome, Inflammation, Gene Expression, severe COVID-19, Inflammatory responses, susceptibility, severity, Peripheral blood, Regulatory, Region, hyperinflammation, Patient, clinical impact, interactions, mechanism, single-cell, IFN-γ, mononuclear cells, individual, severe COVID-19 patients, classical monocytes, chromatin, ChIP, element, inflammatory immune response, Hematopoiesis, immunological, highlight, reported, facilitate, exhibited, dissect, methylated, chromatin architecture, exacerbating, putative target gene, with COVID-19, 【제목키워드】 Transcriptome, severe COVID-19, gene expression signature, Hematopoiesis, analysis,