SARS-CoV-2 infection perturbs enhancer mediated transcriptional regulation of key pathways

Yahel Yedidya, Daniel Davis, Yotam Drier

Research output: Contribution to journalArticlepeer-review

Abstract

Despite extensive studies on the effects of SARS-CoV-2 infection, there is still a lack of understanding of the downstream epigenetic and regulatory alterations in infected cells. In this study, we investigated changes in enhancer acetylation in epithelial lung cells infected with SARS-CoV-2 and their influence on transcriptional regulation and pathway activity. To achieve this, we integrated and reanalyzed data of enhancer acetylation, ex-vivo infection and single cell RNA-seq data from human patients. Our findings revealed coordinated changes in enhancers and transcriptional networks. We found that infected cells lose the WT1 transcription factor and demonstrate disruption of WT1-bound enhancers and of their associated target genes. Downstream targets of WT1 are involved in the regulation of the Wnt signaling and the mitogen-activated protein kinase cascade, which indeed exhibit increased activation levels. These findings may provide a potential explanation for the development of pulmonary fibrosis, a lethal complication of COVID-19. Moreover, we revealed over-acetylated enhancers associated with upregulated genes involved in cell adhesion, which could contribute to cell-cell infection of SARS-CoV-2. Furthermore, we demonstrated that enhancers may play a role in the activation of pro-inflammatory cytokines and contribute to excessive inflammation in the lungs, a typical complication of COVID-19. Overall, our analysis provided novel insights into the cell-autonomous dysregulation of enhancer regulation caused by SARS-CoV-2 infection, a step on the path to a deeper molecular understanding of the disease.

Original languageAmerican English
Pages (from-to)e1011397
JournalPLoS Computational Biology
Volume19
Issue number8
DOIs
StatePublished - 1 Aug 2023

Bibliographical note

Publisher Copyright:
Copyright: © 2023 Yedidya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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