The histone methyltransferase MLL1/KMT2A in monocytes drives coronavirus-associated coagulopathy and inflammation
dc.contributor.author | Sharma, SB | |
dc.contributor.author | Melvin, WJ | |
dc.contributor.author | Audu, CO | |
dc.contributor.author | Bame, M | |
dc.contributor.author | Rhoads, N | |
dc.contributor.author | Wu, W | |
dc.contributor.author | Kanthi, Y | |
dc.contributor.author | Knight, JS | |
dc.contributor.author | Adili, R | |
dc.contributor.author | Holinstat, MA | |
dc.contributor.author | Wakefield, TW | |
dc.contributor.author | Henke, PK | |
dc.contributor.author | Moore, BB | |
dc.contributor.author | Gallagher, KA | |
dc.contributor.author | Obi, AT | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-02-14T15:19:50Z | |
dc.date.available | 2024-02-14 10:19:50 | en |
dc.date.issued | 2023-01-01 | |
dc.identifier.issn | 0006-4971 | |
dc.identifier.issn | 1528-0020 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/36493338 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/175823 | en |
dc.description.abstract | Coronavirus-associated coagulopathy (CAC) is a morbid and lethal sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CAC results from a perturbed balance between coagulation and fibrinolysis and occurs in conjunction with exaggerated activation of monocytes/macrophages (MO/Mφs), and the mechanisms that collectively govern this phenotype seen in CAC remain unclear. Here, using experimental models that use the murine betacoronavirus MHVA59, a well-established model of SARS-CoV-2 infection, we identify that the histone methyltransferase mixed lineage leukemia 1 (MLL1/KMT2A) is an important regulator of MO/Mφ expression of procoagulant and profibrinolytic factors such as tissue factor (F3; TF), urokinase (PLAU), and urokinase receptor (PLAUR) (herein, “coagulopathy-related factors”) in noninfected and infected cells. We show that MLL1 concurrently promotes the expression of the proinflammatory cytokines while suppressing the expression of interferon alfa (IFN-α), a well-known inducer of TF and PLAUR. Using in vitro models, we identify MLL1-dependent NF-κB/RelA–mediated transcription of these coagulation-related factors and identify a context-dependent, MLL1-independent role for RelA in the expression of these factors in vivo. As functional correlates for these findings, we demonstrate that the inflammatory, procoagulant, and profibrinolytic phenotypes seen in vivo after coronavirus infection were MLL1-dependent despite blunted Ifna induction in MO/Mφs. Finally, in an analysis of SARS-CoV-2 positive human samples, we identify differential upregulation of MLL1 and coagulopathy-related factor expression and activity in CD14+ MO/Mφs relative to noninfected and healthy controls. We also observed elevated plasma PLAU and TF activity in COVID-positive samples. Collectively, these findings highlight an important role for MO/Mφ MLL1 in promoting CAC and inflammation. | |
dc.format.medium | Print-Electronic | |
dc.language | eng | |
dc.publisher | American Society of Hematology | |
dc.subject | Rare Diseases | |
dc.subject | Cancer | |
dc.subject | Lung | |
dc.subject | Hematology | |
dc.subject | 2 Aetiology | |
dc.subject | 2.1 Biological and endogenous factors | |
dc.title | The histone methyltransferase MLL1/KMT2A in monocytes drives coronavirus-associated coagulopathy and inflammation | |
dc.type | Article | |
dc.identifier.pmid | 36493338 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/175823/2/The Histone Methyltransferase MLL1KMT2A in Monocytes Drives Coronavirus-Associated Coagulopathy and Inflammation.pdf | |
dc.identifier.doi | 10.1182/blood.2022015917 | |
dc.identifier.doi | https://dx.doi.org/10.7302/6957 | |
dc.identifier.source | Blood | |
dc.description.version | Published version | |
dc.date.updated | 2023-02-14T15:19:45Z | |
dc.identifier.orcid | 0000-0003-3551-2578 | |
dc.identifier.orcid | 0000-0002-3241-5919 | |
dc.identifier.orcid | 0000-0002-4183-8825 | |
dc.identifier.orcid | 0000-0001-8331-5136 | |
dc.identifier.orcid | 0000-0003-0995-9771 | |
dc.identifier.orcid | 0000-0002-1973-9695 | |
dc.identifier.orcid | 0000-0001-5100-1933 | |
dc.identifier.orcid | 0000-0001-7362-2634 | |
dc.identifier.orcid | 0000-0003-3051-745X | |
dc.identifier.orcid | 0000-0002-8791-6980 | |
dc.identifier.orcid | 0000-0001-7613-2366 | |
dc.identifier.startpage | blood.2022015917 | |
dc.identifier.name-orcid | Sharma, SB; 0000-0003-3551-2578 | |
dc.identifier.name-orcid | Melvin, WJ; 0000-0002-3241-5919 | |
dc.identifier.name-orcid | Audu, CO; 0000-0002-4183-8825 | |
dc.identifier.name-orcid | Bame, M | |
dc.identifier.name-orcid | Rhoads, N; 0000-0001-8331-5136 | |
dc.identifier.name-orcid | Wu, W | |
dc.identifier.name-orcid | Kanthi, Y | |
dc.identifier.name-orcid | Knight, JS; 0000-0003-0995-9771 | |
dc.identifier.name-orcid | Adili, R; 0000-0002-1973-9695 | |
dc.identifier.name-orcid | Holinstat, MA; 0000-0001-5100-1933 | |
dc.identifier.name-orcid | Wakefield, TW; 0000-0001-7362-2634 | |
dc.identifier.name-orcid | Henke, PK | |
dc.identifier.name-orcid | Moore, BB; 0000-0003-3051-745X | |
dc.identifier.name-orcid | Gallagher, KA; 0000-0002-8791-6980 | |
dc.identifier.name-orcid | Obi, AT; 0000-0001-7613-2366 | |
dc.working.doi | 10.7302/6957 | en |
dc.owningcollname | Surgery, Department of |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.