EZH2-mediated H3K27me3 inhibits ACE2 expression

Abstract

Available online xxx Keywords: Coronavirus SARS-CoV-2 ACE2 EZH2 H3.3 a b s t r a c tThe outbreak of corona virus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is spreading globally and quickly, leading to emerging health issues. SARS-CoV-2 enters into and infects host cells through its spike glycoprotein recognizing the cell receptor Angiotensin-converting enzyme II (ACE2).Here, we noticed that ACE2 was further enhanced by SARS-CoV-2 infection. Human germ cells and early embryos express high level of ACE2. Notably, RNA-seq result showed that reduction of H3K27me3, but not H3K4/9/36me3, led to upregulation of Ace2 expression in mouse germ cell line GC-2. In agreement with this result, we found in human embryonic stem cells that ACE2 expression was significantly increased in absence of EZH2, the major enzyme catalyzing H3K27me3. ChIP-seq analysis further confirmed decrease of H3K27me3 signal and increase of H3K27ac signal at ACE2 promoter upon EZH2 knockout. Therefore, we propose that EZH2-mediated H3K27me3 at ACE2 promoter region inhibits ACE2 expression in mammalian cells. This regulatory pattern may also exist in other human cells and tissues. Our discovery provides clues for pathogenesis and targeted drug therapy towards ACE2 expression for prevention and adjuvant therapy of COVID-19.

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

“…In agreement with the inverse correlation between ACE2 level and H3K27me3, ACE2 expression in human ESCs was upregulated following EZH2 knock-out (Li Y. et al, 2020). On the other side, recovery of EZH2 restored basal ACE2 levels.…”

“…On the other side, recovery of EZH2 restored basal ACE2 levels. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that EZH2 depletion induced H3K27me3 decrease, with concomitant H3K27ac increase, at ACE2 promoter in human ESCs (Li Y. et al, 2020). The role of H3 methylation and acetylation in the epigenetic regulation of ACE2 was also hypothesized by Pinto et al, who demonstrated that co-morbidities such as hypertension, diabetes, and chronic obstructive lung disease increase ACE2 transcription in the lung (Pinto et al, 2020).…”

“…A recent analysis of public genomic and transcriptomic data outlined the role of histone methylation, a classical epigenetic mark, to regulate ACE2 transcription. Indeed, Li Y. et al (2020) showed that transcription of ACE2 was significantly upregulated when the histone mutant H3K27M was overexpressed to inhibit H3K27me3. Conversely, overexpression of mutant H3K4/9/36M did not change ACE2 transcription.…”

“…As evidence builds up, ACE2 rapidly emerged as a specific target for COVID-19 treatment. Since this enzyme was identified as the SARS-CoV-2 receptor (Zhou et al, 2020), several approaches to address ACE2 mediated infection have been described (Li Y. et al, 2020;Zhang H. et al, 2020), with the aim to prevent host…”

COVID-19: Advances in diagnostic tools, treatment strategies, and vaccine development

“…Given that SARS-CoV-2 utilizes structures such as lipid rafts to mediate its entry process, the authors recommend exploring the possibilities of employing substances like cyclodextrin and sterols to interfere with such viral attachment and entry-enabling mechanisms. Along similar lines of conjecturing prospective therapeutic candidates, EZH2-mediated H3K27me3 at ACE2 promoter regions has been demonstrated to inhibit the expression of ACE2 receptors in mammalian cell lines, as indicated by data from RNA-Seq and CHIP-Seq experiments (Li et al 2020d ).…”