Environmentally-induced mdig contributes to the severity of COVID-19 through fostering expression of SARS-CoV-2 receptor NRPs and glycan metabolism

Abstract

The novel β-coronavirus, SARS-CoV-2, the causative agent of coronavirus disease 2019 , has infected more than 177 million people and resulted in 3.84 million death worldwide. Recent epidemiological studies suggested that some environmental factors, such as air pollution, might be the important contributors to the mortality of COVID-19. However, how environmental exposure enhances the severity of COVID-19 remains to be fully understood. In the present report, we provided evidence showing that mdig, a previously reported environmentally-induced oncogene that antagonizes repressive trimethylation of histone proteins, is an important regulator for SARS-CoV-2 receptors neuropilin-1 (NRP1) and NRP2, cathepsins, glycan metabolism and inflammation, key determinants for viral infection and cytokine storm of the patients. Depletion of mdig in bronchial epithelial cells by CRISPR-Cas-9 gene editing resulted in a decreased expression of NRP1, NRP2, cathepsins, and genes involved in protein glycosylation and inflammation, largely due to a substantial enrichment of lysine 9 and/or lysine 27 trimethylation of histone H3 (H3K9me3/H3K27me3) on these genes as determined by ChIP-seq. Meanwhile, we also validated that environmental factor arsenic is able to induce mdig, NRP1 and NRP2, and genetic disruption of mdig lowered expression of NRP1 and NRP2. Furthermore, mdig may coordinate with the Neanderthal variants linked to an elevated mortality of COVID-19. These data, thus, suggest that mdig is a key mediator for the severity of COVID-19 in response to environmental exposure and targeting mdig may be the one of the effective strategies in ameliorating the symptom and reducing the mortality of COVID-19.

The Unfavorable Clinical Outcome of COVID-19 in Smokers is Mediated by H3K4me3, H3K9me3 and H3K27me3 Histone Marks

“…Recent investigations have traced the footprint of epigenetics back to well before the onset of COVID-19 in a retrograde predisposing circuit, which is extensively influenced by external – or in a more proper sense, environmental – stimuli, such as air pollution and tobacco smoke [ 10 ] that are at the pinnacle of environmental issues in the modern world.…”

“…As biomedical scholars, it is professionally rewarding to know that epigenetic mechanisms alter the common transcriptional bridge between smoking and COVID-19 by trimethylation (me3) of particular lysine (K) residues at H3 and H4 histones [ 10 ] in the form of the heterochromatin-specific H3K9me3, H3K27me3 and H4K20me3 marks, as well as the euchromatin-specific H3K4me3 mark. Although the H3K9me3, H3K27me3 and H4K20me3 fall within the category of repressive histone marks – that is, they negatively regulate the expression of genes upon enrichment – H3K4me3 is an active histone mark that positively regulates transcriptional activity upon enrichment [ 11 ].…”

“…In the context of a presumed interplay between smoking and COVID-19, it is even more interesting when one realizes that all of these histone marks are somehow associated with mdig gene (GenBank: BE441202, https://www.ncbi.nlm.nih.gov/nuccore/BE441202 ) [ 10 ], a lung cancer-related, cell growth-regulating gene spanning ~30,000 base-pairs, located on chromosome 3 that was first identified in the alveolar macrophages of coal miners with a history of exposure to mineral dust. Mdig was essentially speculated to be a type of nuclear protein regulating transcriptional activity by means of chromatin remodeling because it contained several specific domains at its amino terminus known as JmjC domains, which are inherently associated with transcriptional regulation in bacterial and eukaryotic cells.…”

“…Silencing of mdig in human lung epithelial cells was recently shown to result in downregulation of several genes, which are overexpressed in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients, indicating a potential positive regulatory effect for mdig on the genes involved in the pathogenesis of COVID-19 [ 10 ].…”

“…Mdig knockout results in significant enrichment of transcription-repressing histone modifications – namely, H3K9me3, H3K27me3 and H4K20me3 in human lung epithelial cells. In the case of H3K9me3, a near threefold enhancement was observed in mdig -deficient cells [ 10 ]. This appears to be of significant importance, particularly in COVID-19 patients because there is now evidence that H3K9me3 is downregulated at the promoters of certain pro-inflammatory genes driving macrophage-mediated inflammation [ 16 ].…”