ABSTRACT
Development of novel approaches for regulating the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) is becoming increasingly important within the context of the ongoing COVID-19 pandemic since these enzymes play a crucial role in cell infection. In this work we searched for putative ACE2 and TMPRSS2 expression regulation networks mediated by various miRNA isoforms (isomiR) across different human organs using publicly available paired miRNA/mRNA-sequencing data from The Cancer Genome Atlas (TCGA) project. As a result, we identified several miRNA families targeting ACE2 and TMPRSS2 genes in multiple tissues. In particular, we found that lysine-specific demethylase 5B (JARID1B), encoded by the KDM5B gene, can indirectly affect ACE2 / TMPRSS2 expression by repressing transcription of hsa-let-7e / hsa-mir-125a and hsa-mir-141 / hsa-miR-200 miRNA families which are targeting these genes.
Subject(s)
Betacoronavirus , Coronavirus Infections/enzymology , Gene Expression Regulation , MicroRNAs/genetics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/enzymology , RNA, Messenger/genetics , Serine Endopeptidases/genetics , 3' Untranslated Regions , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/virology , Databases, Genetic , Gene Regulatory Networks , Humans , Jumonji Domain-Containing Histone Demethylases/genetics , MicroRNAs/metabolism , Nuclear Proteins/genetics , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , RNA Isoforms/genetics , RNA, Messenger/metabolism , RNA-Seq , Repressor Proteins/genetics , SARS-CoV-2 , Serine Endopeptidases/metabolism , Single-Cell AnalysisABSTRACT
Obesity patients are more susceptible to develop COVID-19 severe outcome due to the role of angiotensin-converting enzyme 2 (ACE2) in the viral infection. ACE2 is regulated in the human cells by different genes associated with increased (TLR3, HAT1, HDAC2, KDM5B, SIRT1, RAB1A, FURIN and ADAM10) or decreased (TRIB3) virus replication. RNA-seq data revealed 14857 genes expressed in human subcutaneous adipocytes, including genes mentioned above. Irisin treatment increased by 3-fold the levels of TRIB3 transcript and decreased the levels of other genes. The decrease in FURIN and ADAM10 expression enriched diverse biological processes, including extracellular structure organization. Our results, in human subcutaneous adipocytes cell culture, indicate a positive effect of irisin on the expression of multiple genes related to viral infection by SARS-CoV-2; furthermore, translatable for other tissues and organs targeted by the novel coronavirus and present, thus, promising approaches for the treatment of COVID-19 infection as therapeutic strategy to decrease ACE2 regulatory genes.