The Neat Dance of COVID-19: NEAT1, DANCR, and Co-Modulated Cholinergic RNAs Link to Inflammation

Abstract

The COVID-19 pandemic exerts inflammation-related parasympathetic complications and post-infection manifestations with major inter-individual variability. To seek the corresponding transcriptomic origins for the impact of COVID-19 infection and its aftermath consequences, we sought the relevance of long and short non-coding RNAs (ncRNAs) for susceptibility to COVID-19 infection. We selected inflammation-prone men and women of diverse ages among the cohort of Genome Tissue expression (GTEx) by mining RNA-seq datasets from their lung, and blood tissues, followed by quantitative qRT-PCR, bioinformatics-based network analyses and thorough statistics compared to brain cell culture and infection tests with COVID-19 and H1N1 viruses. In lung tissues from 57 inflammation-prone, but not other GTEx donors, we discovered sharp declines of the lung pathology-associated ncRNA DANCR and the nuclear paraspeckles forming neuroprotective ncRNA NEAT1. Accompanying increases in the acetylcholine-regulating transcripts capable of controlling inflammation co-appeared in SARS-CoV-2 infected but not H1N1 influenza infected lung cells. The lung cells-characteristic DANCR and NEAT1 association with inflammation-controlling transcripts could not be observed in blood cells, weakened with age and presented sex-dependent links in GTEx lung RNA-seq dataset. Supporting active involvement in the inflammatory risks accompanying COVID-19, DANCR’s decline associated with decrease of the COVID-19-related cellular transcript ACE2 and with sex-related increases in coding transcripts potentiating acetylcholine signaling. Furthermore, transcription factors (TFs) in lung, brain and cultured infected cells created networks with the candidate transcripts, indicating tissue-specific expression patterns. Supporting links of post-infection inflammatory and cognitive damages with cholinergic mal-functioning, man and woman-originated cultured cholinergic neurons presented differentiation-related increases of DANCR and NEAT1 targeting microRNAs. Briefly, changes in ncRNAs and TFs from inflammation-prone human lung tissues, SARS-CoV-2-infected lung cells and man and woman-derived differentiated cholinergic neurons reflected the inflammatory pathobiology related to COVID-19. By shifting ncRNA differences into comparative diagnostic and therapeutic profiles, our RNA-sequencing based Resource can identify ncRNA regulating candidates for COVID-19 and its associated immediate and predicted long-term inflammation and neurological complications, and sex-related therapeutics thereof. Our findings encourage diagnostics of involved tissue, and further investigation of NEAT1-inducing statins and anti-cholinergic medications in the COVID-19 context.

Long Noncoding RNAs as Emerging Regulators of COVID-19

“…These results reveal the role of lncRNAs in innate immunity and suggest that NEAT1 is a common mediator of inflammatory signaling induction. Furthermore, Chanan Meydan et al showed that sharp declines in the lung pathology-associated lncRNA DANCR and the nuclear paraspeckles forming the neuroprotective lncRNA NEAT1 are potentially associated with the susceptibility to and outcome of COVID-19 infection (46). The inflammationmodulating lncRNA DANCR, as a potential chief regulator, is responsible for the surveillance of inflammatory cholinergic blockade, thus supporting the maintenance of a delicate balance between pro-inflammatory and anti-inflammatory pathways in SARS-CoV-2-affected lung and brain tissues.…”

“…This research provides arguments to consider that ncRNA-mRNA network. The interconnectivity of this network may be elucidated upon examining shared components such as miR-135b-5p, miR-656-3p, and miR-19a-3p, as some may interact with key relevant downstream mediators such as TNF and IL-6 to affect inflammation, leading to COVID-19 ( 46 ).…”

“…Moreover, some viruses can spread from the lungs to the central nervous system via a blood-borne route. The lncRNA DANCR is potentially the chief regulator responsible for the surveillance of inflammatory cholinergic blockades and thus plays distinct roles in pneumonia and neuroinflammation ( 46 ). Acetylcholine interacts with macrophages to inhibit the synthesis of inflammatory cytokines.…”

Identification of an miRNA Regulatory Network and Candidate Markers for Ischemic Stroke Related to Diabetes

“… 40 , 41 The miR-576-3p has been reported to induce interferon production, and gene therapy to restore interferon production may improve prognosis after ischemic stroke. 42 , 43 The miR-665 is down-regulated in T2DM patients and up-regulated in stroke patients. 44 , 45 This suggests that the four miRNAs that we identified – especially miR-576-3p, with the most target genes – may be risk factors and markers for the development of ischemic stroke in T2DM patients.…”

Distinct Mucoinflammatory Phenotype and the Immunomodulatory Long Noncoding Transcripts Associated with SARS-CoV-2 Airway Infection

“…The copyright holder for this preprint this version posted May 18, 2021. ; https://doi.org/10.1101/2021.05.13.21257152 doi: medRxiv preprint immune dysfunction (14)(15)(16)(17), there are limited studies on the respiratory epithelia specific lncRNAs and their role in SARS-CoV-2 infection (18,19). As such, in this study, we assessed acute mucoinflammatory and immunomodulatory responses, including lncRNA expressions in a 3D airway tissue model of acute SARS-CoV-2 infection and COVID-19 patient nasopharyngeal samples to gain novel insights into early innate responses of human respiratory cells.…”