Evolutionarily Conserved Long Non-coding RNA Regulates Gene Expression in Cytokine Storm During COVID-19

Abstract

Coronavirus is a family of viruses including alpha-, beta-, gamma-, delta-coronaviruses. Only alpha- and betacoronaviruses have been observed to infect humans. Past outbreaks of SARS-CoV and MERS-CoV, both betacoronavirus, are the result of a spillover from animals. Recently, a new strain termed SARS-CoV-2 emerged in December 2019 in Wuhan, China. Severe cases of COVID-19, the disease caused by SARS-CoV-2, lead to acute respiratory distress syndrome (ARDS). One contributor to the development of ARDS is cytokine storm, an overwhelming inflammatory immune response. Long non-coding RNAs (lncRNAs) are genetic regulatory elements that, among many functions, alter gene expression and cellular processes. lncRNAs identified to be pertinent in COVID-19 cytokine storm have the potential to serve as disease markers or drug targets. This project aims to computationally identify conserved lncRNAs potentially regulating gene expression in cytokine storm during COVID-19. We found 22 lncRNAs that can target 10 cytokines overexpressed in COVID-19 cytokine storm, 8 of which targeted two or more cytokine storm cytokines. In particular, the lncRNA non-coding RNA activated by DNA damage (NORAD), targeted five out of the ten identified cytokine storm cytokines, and is evolutionarily conserved across multiple species. These lncRNAs are ideal candidates for further in vitro and in vivo analysis.

Long Noncoding RNAs as Emerging Regulators of COVID-19

“…Of note, several lncRNA can directly regulate the transcription of cytokines. Recently, Oranrewaju B. et al identified 22 lncRNAs that target 10 cytokines overexpressed in COVID-19 cytokine storms (44). In particular, the lncRNA NORAD, activated by DNA damage, targets five of the ten cytokines in cytokine storms (interleukin (IL)-6, IL-10, CSF3, tumor necrosis factor (TNF)-a and CXCL10), which is more than other identified lncRNAs.…”

Regulatory Network of miRNA, lncRNA, Transcription Factor and Target Immune Response Genes in Bovine Mastitis

“…Furthermore, we identi ed important interactions between certain lncRNAs and mRNAs that could mediate host immune response at the post-transcriptional level. lncRNAs are becoming known to be involved in several biogenetic processes that may regulate disease pathogenesis 14,44 . We hypothesized that lncRNAs that bind to multiple mRNA target sequences could serve as drug targets and have the potential to modify or regulate immune signaling pathways, ameliorating the over-or under-production of cytokines or chemokine during infection.…”

“…Functional and pathway analysis of candidate genes associated with immune response to bovine mastitis Functional enrichment analysis, using geneontology.org, was performed on the 16 candidate genes to determine the molecular functions, biological processes and cellular components the genes are involved in as described 14,59 , with slight changes. Using the fold enrichment of greater than 100, the false discovery rate (FDR) of <10 -5 , and the p-value of <10 -7 , we catalogue the biological processes and cellular components.…”

“…LncRNAs play key roles in regulating several cellular and developmental processes, including genomic imprinting, DNA methylation, splicing and chromatin modi cation 11,12 . With an abundance of binding sites for miRNA and mRNA, lncRNA can act as ceRNA (competing endogenous RNA) and are signi cant regulatory elements in post-transcriptional gene expression 13,14 . For example, lncRNA adipocyte differentiation-associated long noncoding RNA (ADNCR) targets miR-204 signi cantly regulating Sirtuin 1 (SIRT1) gene expression at the mRNA and protein level, inhibiting adipogenesis in the process 15 .…”

Decoding LncRNAs

“…Expression of lncRNAs changes in response to various pathogens—likely due to deregulation of host immune responses [ 212 , 213 , 214 ]. There seems to be a footprint pattern of lncRNAs expression depending of the pathogen, as has been shown by studies with Escherichia coli [ 215 ], Salmonella typhimurium [ 216 ], Mycobacterium tuberculosis [ 217 , 218 , 219 , 220 ], Campylobacter oncisus [ 221 ], or Helicobacter pylori [ 222 , 223 ], also after infection by the human immunodeficiency virus (HIV) [ 224 ], ZIKA virus, Sendai virus, hepatitis C virus [ 205 ] and COVID-19 [ 225 ].…”