# Long non-coding RNA enhances SARS-CoV-2-mediated apoptosis through epigenetic repression of angiotensin-converting enzyme 2

## TL;DR

This study reveals how a long non-coding RNA called EAS1 contributes to organ damage in SARS-CoV-2 infection by reducing ACE2 levels through epigenetic changes.

## Contribution

The study identifies a novel epigenetic mechanism by which SARS-CoV-2 represses ACE2 expression via the lncRNA EAS1.

## Key findings

- EAS1 is upregulated in multiple coronavirus infections and recruits GCN5 to acetylate PGC1β.
- EAS1-mediated repression of ACE2 worsens apoptosis in response to TNF-α and hypoxia.
- EAS1's role in ACE2 suppression suggests it could be a therapeutic target for reducing organ injury in COVID-19.

## Abstract

Despite its critical role in organ protection, angiotensin-converting enzyme 2 (ACE2) is paradoxically downregulated during SARS-CoV-2 infection, contributing to multi-organ dysfunction in COVID-19. The mechanisms driving this loss, particularly those mediated by long non-coding RNAs (lncRNAs), are unknown. Through transcriptomic analysis, we identified that the lncRNA EPB41L4A-AS1 (EAS1) is consistently upregulated upon infection by multiple coronaviruses, including SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV-229E. Mechanistically, SARS-CoV-2 infection activates HIF-1α, which binds to an enhancer element within the EAS1 locus to drive its expression. Subsequently, EAS1 recruits the acetyltransferase GCN5 to catalyze the acetylation of the transcriptional coactivator PGC1β. This modification disrupts the interaction between PGC1β and the transcription factor PPARγ, thereby impairing PPARγ-mediated transactivation of the ACE2 gene and leading to its transcriptional repression. Functionally, we demonstrate that this EAS1-mediated suppression of ACE2 exacerbates cellular apoptosis induced by TNF-α and hypoxia, two key pathological features of severe COVID-19. Our study unveils a novel epigenetic pathway through which SARS-CoV-2 dysregulates ACE2 expression and promotes cellular damage. Given the persistent threat of recurrent coronavirus spillovers, the conserved upregulation of EAS1 across distinct coronavirus genera suggests it may represent a potential therapeutic target for mitigating organ injury in COVID-19. Furthermore, our findings that the EAS1-ACE2 axis mediates apoptosis in response to hypoxia and cytokine signaling warrant future investigation into its role in other pathological contexts beyond viral infection.