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As MYLK coding SNPs are associated with severe inflammatory disorders (asthma, acute respiratory distress syndrome (ARDS)), we explored clinically relevant inflammatory stimuli and promoter SNPs in nmMLCK promoter regulation. Methods: Full-length or serially deleted MYLK luciferase reporter promoter activities were measured in human lung endothelial cells (ECs). SNP-containing non-muscle MYLK (nmMYLK) DNA fragments were generated and nmMYLK promoter binding by transcription factors (TFs) detected by protein\u2013DNA electrophoretic mobility shift assay (EMSA). Promoter demethylation was evaluated by 5-aza-2\u2032-deoxycytidine (5-Aza). A preclinical mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) was utilized for nmMLCK validation. Results: Lung EC levels of nmMLCK were significantly increased in LPS-challenged mice and LPS, tumor necrosis factor-\u03b1 (TNF-\u03b1), 18% cyclic stretch (CS) and 5-Aza each significantly up-regulated EC nmMYLK promoter activities. EC exposure to FG-4592, a prolyl hydroxylase inhibitor that increases hypoxia-inducible factor (HIF) expression, increased nmMYLK promoter activity, confirmed by HIF1\u03b1\/HIF2\u03b1 silencing. nmMYLK promoter deletion studies identified distal inhibitory and proximal enhancing promoter regions as well as mechanical stretch-, LPS- and TNF\u03b1-inducible regions. Insertion of ARDS-associated SNPs (rs2700408, rs11714297) significantly increased nmMYLK promoter activity via increased transcription binding (glial cells missing homolog 1 (GCM1) and intestine-specific homeobox (ISX), respectively). Finally, the MYLK rs78755744 SNP (\u2212261G\/A), residing within a nmMYLK CpG island, significantly attenuated 5-Aza-induced promoter activity. Conclusion: These findings indicate nmMYLK transcriptional regulation by clinically relevant inflammatory factors and ARDS-associated nmMYLK promoter variants are consistent with nmMLCK as a therapeutic target in severe inflammatory disorders.<\/jats:p>","DOI":"10.1042\/cs20201448","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T13:39:16Z","timestamp":1617284356000},"page":"963-977","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Genetic and epigenetic regulation of the non-muscle myosin light chain kinase isoform by lung inflammatory factors and mechanical stress"],"prefix":"10.1042","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4226-8294","authenticated-orcid":false,"given":"Xiaoguang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda\u00a0L.","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Arizona, Tucson, AZ, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saad","family":"Sammani","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadeo","family":"Bermudez","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven\u00a0M.","family":"Dudek","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Illinois Chicago, Chicago, IL, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara\u00a0M.","family":"Camp","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6934-0420","authenticated-orcid":false,"given":"Joe\u00a0G.N.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Arizona, Tucson, AZ, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2021,4,14]]},"reference":[{"key":"2021113011203875300_B1","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathological findings of COVID-19 associated with acute respiratory distress syndrome","volume":"8","author":"Xu","year":"2020","journal-title":"Lancet Respir. 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