RESUMEN
Smoking could predispose individuals to a more severe COVID-19 by upregulating a particular gene known as mdig, which is mediated through a number of well-known histone modifications. Smoking might regulate the transcription-activating H3K4me3 mark, along with the transcription-repressing H3K9me3 and H3K27me3 marks, in a way to favor SARS-CoV-2 entry by enhancing the expression of ACE2, NRP1 and NRP2, AT1R, CTSD and CTSL, PGE2 receptors 2-4, SLC6A20 and IL-6, all of which interact either directly or indirectly with important receptors, facilitating viral entry in COVID-19.
Lay abstract The role of smoking in development of several respiratory diseases has been clearly established. A significant proportion of these deleterious effects is mediated through epigenetic mechanisms, particularly histone modifications. Recent evidence indicates that smoking induces the expression of a mediator known as mdig, which in turn alters the transcription of several key proteins that have been implicated in development of COVID-19.
Asunto(s)
COVID-19/genética , Dioxigenasas/genética , Epigénesis Genética , Histona Demetilasas/genética , Histonas/genética , Proteínas Nucleares/genética , Procesamiento Proteico-Postraduccional , Fumar/genética , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/diagnóstico , COVID-19/metabolismo , COVID-19/virología , Catepsina D/genética , Catepsina D/metabolismo , Catepsina L/genética , Catepsina L/metabolismo , Dioxigenasas/metabolismo , Histona Demetilasas/metabolismo , Histonas/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Metilación , Neuropilina-1/genética , Neuropilina-1/metabolismo , Neuropilina-2/genética , Neuropilina-2/metabolismo , Proteínas Nucleares/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/metabolismo , Factores de Riesgo , SARS-CoV-2/genética , SARS-CoV-2/crecimiento & desarrollo , SARS-CoV-2/metabolismo , Fumar/metabolismo , Fumar/patología , Internalización del VirusAsunto(s)
COVID-19/inmunología , Síndrome de Liberación de Citoquinas/prevención & control , Histona Demetilasas/antagonistas & inhibidores , SARS-CoV-2/efectos de los fármacos , COVID-19/genética , COVID-19/virología , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/genética , Citocinas/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Histona Demetilasas/genética , Histona Demetilasas/inmunología , Humanos , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Sepsis/tratamiento farmacológico , Sepsis/virología , Tratamiento Farmacológico de COVID-19RESUMEN
The novel ß-coronavirus, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), 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.