Single-cell multiomics reveal divergent effects of DNMT3A- and TET2-mutant clonal hematopoiesis in inflammatory response
Abstract: DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematologic neoplasms. Although individ...
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Elsevier
2025-01-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S247395292400702X |
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| author | Wazim Mohammed Ismail Jenna A. Fernandez Moritz Binder Terra L. Lasho Minsuk Kim Susan M. Geyer Amelia Mazzone Christy M. Finke Abhishek A. Mangaonkar Jeong-Heon Lee Liguo Wang Kwan Hyun Kim Vernadette A. Simon Fariborz Rakhshan Rohakthar Amik Munankarmy Seul Kee Byeon Susan M. Schwager Jonathan J. Harrington Melissa R. Snyder Keith D. Robertson Akhilesh Pandey Eric D. Wieben Nicholas Chia Alexandre Gaspar-Maia Mrinal M. Patnaik |
| author_facet | Wazim Mohammed Ismail Jenna A. Fernandez Moritz Binder Terra L. Lasho Minsuk Kim Susan M. Geyer Amelia Mazzone Christy M. Finke Abhishek A. Mangaonkar Jeong-Heon Lee Liguo Wang Kwan Hyun Kim Vernadette A. Simon Fariborz Rakhshan Rohakthar Amik Munankarmy Seul Kee Byeon Susan M. Schwager Jonathan J. Harrington Melissa R. Snyder Keith D. Robertson Akhilesh Pandey Eric D. Wieben Nicholas Chia Alexandre Gaspar-Maia Mrinal M. Patnaik |
| author_sort | Wazim Mohammed Ismail |
| collection | DOAJ |
| description | Abstract: DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematologic neoplasms. Although individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here, we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity (acute respiratory distress syndrome [ARDS]) and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant (DNMT3Amt) CH on COVID-19–related ARDS and mortality. Using single-cell proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid lineage cells. Using single-cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of interleukin-32 (IL-32), a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single-cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Hence, we demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19–related ARDS and mortality. DNMT3Amt CH in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can thus serve as a potential biomarker for adverse outcomes in COVID-19. |
| format | Article |
| id | doaj-art-a4c20f89ef7348fd8399c44063faec82 |
| institution | Kabale University |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-a4c20f89ef7348fd8399c44063faec822025-01-18T05:05:00ZengElsevierBlood Advances2473-95292025-01-0192402416Single-cell multiomics reveal divergent effects of DNMT3A- and TET2-mutant clonal hematopoiesis in inflammatory responseWazim Mohammed Ismail0Jenna A. Fernandez1Moritz Binder2Terra L. Lasho3Minsuk Kim4Susan M. Geyer5Amelia Mazzone6Christy M. Finke7Abhishek A. Mangaonkar8Jeong-Heon Lee9Liguo Wang10Kwan Hyun Kim11Vernadette A. Simon12Fariborz Rakhshan Rohakthar13Amik Munankarmy14Seul Kee Byeon15Susan M. Schwager16Jonathan J. Harrington17Melissa R. Snyder18Keith D. Robertson19Akhilesh Pandey20Eric D. Wieben21Nicholas Chia22Alexandre Gaspar-Maia23Mrinal M. Patnaik24Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNDivision of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN; Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MNDivision of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MNDepartment of Quantitative Health Sciences, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNDivision of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MNDivision of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MNDepartment of Quantitative Health Sciences, Mayo Clinic, Rochester, MN; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MNMedical Genome Facility, Genome Analysis Core, Mayo Clinic, Rochester, MNMedical Genome Facility, Genome Analysis Core, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNDivision of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MNDepartment of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MNDepartment of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Alexandre Gaspar-Maia, Mayo Clinic College of Medicine and Science, Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905;Department of Laboratory Medicine and Pathology, Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN; Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN; Correspondence: Mrinal M. Patnaik, Mayo Clinic College of Medicine and Science, Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905;Abstract: DNMT3A and TET2 are epigenetic regulator genes commonly mutated in age-related clonal hematopoiesis (CH). Despite having opposed epigenetic functions, these mutations are associated with increased all-cause mortality and a low risk for progression to hematologic neoplasms. Although individual impacts on the epigenome have been described using different model systems, the phenotypic complexity in humans remains to be elucidated. Here, we make use of a natural inflammatory response occurring during coronavirus disease 2019 (COVID-19), to understand the association of these mutations with inflammatory morbidity (acute respiratory distress syndrome [ARDS]) and mortality. We demonstrate the age-independent, negative impact of DNMT3A mutant (DNMT3Amt) CH on COVID-19–related ARDS and mortality. Using single-cell proteogenomics we show that DNMT3A mutations involve myeloid and lymphoid lineage cells. Using single-cell multiomics sequencing, we identify cell-specific gene expression changes associated with DNMT3A mutations, along with significant epigenomic deregulation affecting enhancer accessibility, resulting in overexpression of interleukin-32 (IL-32), a proinflammatory cytokine that can result in inflammasome activation in monocytes and macrophages. Finally, we show with single-cell resolution that the loss of function of DNMT3A is directly associated with increased chromatin accessibility in mutant cells. Hence, we demonstrate the negative prognostic impact of DNMT3Amt CH on COVID-19–related ARDS and mortality. DNMT3Amt CH in the context of COVID-19, was associated with inflammatory transcriptional priming, resulting in overexpression of IL32. This overexpression was secondary to increased chromatic accessibility, specific to DNMT3Amt CH cells. DNMT3Amt CH can thus serve as a potential biomarker for adverse outcomes in COVID-19.http://www.sciencedirect.com/science/article/pii/S247395292400702X |
| spellingShingle | Wazim Mohammed Ismail Jenna A. Fernandez Moritz Binder Terra L. Lasho Minsuk Kim Susan M. Geyer Amelia Mazzone Christy M. Finke Abhishek A. Mangaonkar Jeong-Heon Lee Liguo Wang Kwan Hyun Kim Vernadette A. Simon Fariborz Rakhshan Rohakthar Amik Munankarmy Seul Kee Byeon Susan M. Schwager Jonathan J. Harrington Melissa R. Snyder Keith D. Robertson Akhilesh Pandey Eric D. Wieben Nicholas Chia Alexandre Gaspar-Maia Mrinal M. Patnaik Single-cell multiomics reveal divergent effects of DNMT3A- and TET2-mutant clonal hematopoiesis in inflammatory response Blood Advances |
| title | Single-cell multiomics reveal divergent effects of DNMT3A- and TET2-mutant clonal hematopoiesis in inflammatory response |
| title_full | Single-cell multiomics reveal divergent effects of DNMT3A- and TET2-mutant clonal hematopoiesis in inflammatory response |
| title_fullStr | Single-cell multiomics reveal divergent effects of DNMT3A- and TET2-mutant clonal hematopoiesis in inflammatory response |
| title_full_unstemmed | Single-cell multiomics reveal divergent effects of DNMT3A- and TET2-mutant clonal hematopoiesis in inflammatory response |
| title_short | Single-cell multiomics reveal divergent effects of DNMT3A- and TET2-mutant clonal hematopoiesis in inflammatory response |
| title_sort | single cell multiomics reveal divergent effects of dnmt3a and tet2 mutant clonal hematopoiesis in inflammatory response |
| url | http://www.sciencedirect.com/science/article/pii/S247395292400702X |
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