دورية أكاديمية
Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic-Epigenetic Cross-Talk.
العنوان: | Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic-Epigenetic Cross-Talk. |
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المؤلفون: | Greenwood DL; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., Ramsey HE; Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Nguyen PTT; Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.; Neuroscience Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA., Patterson AR; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., Voss K; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., Bader JE; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., Sugiura A; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., Bacigalupa ZA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN., Schaefer S; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., Ye X; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., Dahunsi DO; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., Madden MZ; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN., Wellen KE; Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Savona MR; Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN; and.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN., Ferrell PB; Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN; and.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN., Rathmell JC; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN.; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN; and.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN. |
المصدر: | ImmunoHorizons [Immunohorizons] 2022 Dec 01; Vol. 6 (12), pp. 837-850. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Association of Immunologists, Inc Country of Publication: United States NLM ID: 101708159 Publication Model: Print Cited Medium: Internet ISSN: 2573-7732 (Electronic) Linking ISSN: 25737732 NLM ISO Abbreviation: Immunohorizons Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: Rockville, Maryland : American Association of Immunologists, Inc., [2017]- |
مواضيع طبية MeSH: | ATP Citrate (pro-S)-Lyase*/deficiency , ATP Citrate (pro-S)-Lyase*/genetics , Epigenesis, Genetic* , Myelopoiesis*/genetics , Chromatin Assembly and Disassembly*, Animals ; Mice ; Acetyl Coenzyme A/genetics ; Acetyl Coenzyme A/metabolism ; Chromatin/metabolism |
مستخلص: | Hematopoiesis integrates cytokine signaling, metabolism, and epigenetic modifications to regulate blood cell generation. These processes are linked, as metabolites provide essential substrates for epigenetic marks. In this study, we demonstrate that ATP citrate lyase (Acly), which metabolizes citrate to generate cytosolic acetyl-CoA and is of clinical interest, can regulate chromatin accessibility to limit myeloid differentiation. Acly was tested for a role in murine hematopoiesis by small-molecule inhibition or genetic deletion in lineage-depleted, c-Kit-enriched hematopoietic stem and progenitor cells from Mus musculus. Treatments increased the abundance of cell populations that expressed the myeloid integrin CD11b and other markers of myeloid differentiation. When single-cell RNA sequencing was performed, we found that Acly inhibitor-treated hematopoietic stem and progenitor cells exhibited greater gene expression signatures for macrophages and enrichment of these populations. Similarly, the single-cell assay for transposase-accessible chromatin sequencing showed increased chromatin accessibility at genes associated with myeloid differentiation, including CD11b, CD11c, and IRF8. Mechanistically, Acly deficiency altered chromatin accessibility and expression of multiple C/EBP family transcription factors known to regulate myeloid differentiation and cell metabolism, with increased Cebpe and decreased Cebpa and Cebpb. This effect of Acly deficiency was accompanied by altered mitochondrial metabolism with decreased mitochondrial polarization but increased mitochondrial content and production of reactive oxygen species. The bias to myeloid differentiation appeared due to insufficient generation of acetyl-CoA, as exogenous acetate to support alternate compensatory pathways to produce acetyl-CoA reversed this phenotype. Acly inhibition thus can promote myelopoiesis through deprivation of acetyl-CoA and altered histone acetylome to regulate C/EBP transcription factor family activity for myeloid differentiation. (Copyright © 2022 The Authors.) |
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معلومات مُعتمدة: | F31 HL152529 United States HL NHLBI NIH HHS; K00 CA234920 United States CA NCI NIH HHS; R01 AI153167 United States AI NIAID NIH HHS; R01 DK116005 United States DK NIDDK NIH HHS; R01 DK105550 United States DK NIDDK NIH HHS; T32 DK101003 United States DK NIDDK NIH HHS; F30 CA239367 United States CA NCI NIH HHS; T32 GM007347 United States GM NIGMS NIH HHS; K23 HL138291 United States HL NHLBI NIH HHS; R01 CA217987 United States CA NCI NIH HHS |
المشرفين على المادة: | 72-89-9 (Acetyl Coenzyme A) EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase) 0 (Chromatin) |
تواريخ الأحداث: | Date Created: 20221222 Date Completed: 20230111 Latest Revision: 20231202 |
رمز التحديث: | 20240628 |
مُعرف محوري في PubMed: | PMC9935084 |
DOI: | 10.4049/immunohorizons.2200086 |
PMID: | 36547387 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2573-7732 |
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DOI: | 10.4049/immunohorizons.2200086 |