A transcription regulatory network within the ACE2 locus may promote a pro-viral environment for SARS-CoV-2 by modulating expression of host factors

Tayaza Fadason; Sreemol Gokuladhas; Evgeniia Golovina; Daniel Ho; Sophie Farrow; Denis Nyaga; Hong Pan; Neerja Karnani; Conroy Wong; Antony Cooper; William Schierding; Justin M. O’Sullivan

The ACE2 protein is highly expressed in cardiovascular and lung type II alveolar epithelial 54 cells [3, 7, 8] , where ACE2 is a primary modulator of the renin-angiotensin (RAS) system that 55 regulates blood flow, pressure and fluid homeostasis [9] . The ACE2 protein and the products 56 of the reactions it catalyses have also been implicated in immune responses and anti-57 inflammatory pathways [10] [11] [12] . 58 SARS-CoV infection reduces ACE2 gene expression and this is thought to contribute to severe 59 acute respiratory failure [4] by triggering an imbalance in the RAS system that causes a loss of 60 fluid homeostasis, induces inflammatory responses [10, 13, 14] , and results in severe acute 61 injury in heart and lung [3,15,16]. As mentioned above, both SARS-CoV and SARS-CoV-2 62 utilize the ACE2 protein for cell entry. Poor prognoses in elderly SARS-CoV-2 patients (≥65 63 years old) are frequently associated with a pre-existing reduction in ACE2 expression and 64 imbalance in ACE2-related host derived pathways [17, 18] . ACE2 is an X-linked gene whose 65 expression is regulated by chromatin structure. Brg1, a chromatin remodeler, and the FoxM1 66 transcription factor recognize the ACE2 promoter and reduce expression through a mechanism 67 NF-kB regulation and pyrimidine synthesis, 94 respectively. VSP13C, encoding a factor required for late stage endosome maturation, is also 95 controlled by a putative enhancer located in intron 11 of BMX, adjacent to ACE2. We propose 96 that ACE2 repression by SARS-CoV-2 trips a chromatin-based switch that coordinates the 97 activity of these regulatory elements and thus the genes they control. Collectively, these 98 changes inadvertently lead to the development of a pro-viral replication environment. The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.14.042002 doi: bioRxiv preprint