FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells.
Autor: | Wong D; Department of Biochemistry and Molecular Genetics (D.W., C.Y., J.V.M., A.M., C.L.M.), University of Virginia, Charlottesville. A.I.; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I.; Robert M. Berne Cardiovascular Research Center (D.W., R.N.P., M. Kuppusamy, S.K.S., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Auguste G; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Lino Cardenas CL; Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (C.L.L.C., R.M.)., Turner AW; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Chen Y; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Song Y; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Ma L; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology (L. Ma, J.L.M.B.), Icahn School of Medicine at Mount Sinai, New York., Perry RN; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I.; Robert M. Berne Cardiovascular Research Center (D.W., R.N.P., M. Kuppusamy, S.K.S., M.C., C.L.M.), University of Virginia, Charlottesville. A.I.; Department of Biomedical Engineering (R.N.P., M.C.), University of Virginia, Charlottesville. A.I., Aherrahrou R; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I.; Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland (R.A.).; Institute for Cardiogenetics, Universität zu Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany, University Heart Centre Lübeck, Lübeck, Germany (R.A.)., Kuppusamy M; Robert M. Berne Cardiovascular Research Center (D.W., R.N.P., M. Kuppusamy, S.K.S., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Yang C; Department of Biochemistry and Molecular Genetics (D.W., C.Y., J.V.M., A.M., C.L.M.), University of Virginia, Charlottesville. A.I.; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Mosquera JV; Department of Biochemistry and Molecular Genetics (D.W., C.Y., J.V.M., A.M., C.L.M.), University of Virginia, Charlottesville. A.I.; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Dube CJ; Department of Microbiology, Immunology, and Cancer Biology (C.J.D.), University of Virginia, Charlottesville. A.I., Khan MD; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Palmore M; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I., Kalra J; Department of Molecular Physiology and Biological Physics (J.K., S.K.S.), University of Virginia, Charlottesville. A.I., Kavousi M; Department of Epidemiology, Erasmus University Medical Center, the Netherlands (M. Kavousi)., Peyser PA; Department of Epidemiology, University of Michigan, Ann Arbor (P.A.P.)., Matic L; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (L. Matic, U.H.)., Hedin U; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (L. Matic, U.H.)., Manichaikul A; Department of Biochemistry and Molecular Genetics (D.W., C.Y., J.V.M., A.M., C.L.M.), University of Virginia, Charlottesville. A.I.; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I.; Department of Public Health Sciences (A.M.), University of Virginia, Charlottesville. A.I., Sonkusare SK; Robert M. Berne Cardiovascular Research Center (D.W., R.N.P., M. Kuppusamy, S.K.S., M.C., C.L.M.), University of Virginia, Charlottesville. A.I.; Department of Molecular Physiology and Biological Physics (J.K., S.K.S.), University of Virginia, Charlottesville. A.I., Civelek M; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I.; Robert M. Berne Cardiovascular Research Center (D.W., R.N.P., M. Kuppusamy, S.K.S., M.C., C.L.M.), University of Virginia, Charlottesville. A.I.; Department of Biomedical Engineering (R.N.P., M.C.), University of Virginia, Charlottesville. A.I., Kovacic JC; Cardiovascular Research Institute (J.C.K.), Icahn School of Medicine at Mount Sinai, New York.; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia (J.C.K.).; St. Vincent's Clinical School, University of New South Wales, Sydney, Australia (J.C.K.)., Björkegren JLM; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology (L. Ma, J.L.M.B.), Icahn School of Medicine at Mount Sinai, New York.; Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Huddinge, Sweden (J.L.M.B.)., Malhotra R; Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (C.L.L.C., R.M.)., Miller CL; Department of Biochemistry and Molecular Genetics (D.W., C.Y., J.V.M., A.M., C.L.M.), University of Virginia, Charlottesville. A.I.; Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I.; Robert M. Berne Cardiovascular Research Center (D.W., R.N.P., M. Kuppusamy, S.K.S., M.C., C.L.M.), University of Virginia, Charlottesville. A.I. |
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Jazyk: | angličtina |
Zdroj: | Circulation research [Circ Res] 2023 Apr 28; Vol. 132 (9), pp. 1144-1161. Date of Electronic Publication: 2023 Apr 05. |
DOI: | 10.1161/CIRCRESAHA.122.321692 |
Abstrakt: | Background: Genome-wide association studies have identified hundreds of loci associated with common vascular diseases, such as coronary artery disease, myocardial infarction, and hypertension. However, the lack of mechanistic insights for many GWAS loci limits their translation into the clinic. Among these loci with unknown functions is UFL1 -four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 ( FHL5 ; chr6q16.1), which reached genome-wide significance in a recent coronary artery disease/ myocardial infarction GWAS meta-analysis. UFL1-FHL5 is also associated with several vascular diseases, consistent with the widespread pleiotropy observed for GWAS loci. Methods: We apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and ex vivo analysis of human coronary artery tissues to implicate FHL5 as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments in coronary artery smooth muscle cells. Results: We prioritized FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through expression quantitative trait locus colocalization methods. FHL5 gene expression was enriched in the smooth muscle cells and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating smooth muscle cell contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream coronary artery disease/myocardial infarction loci, such as FOXL1 and FN1 that have roles in vascular remodeling. Conclusions: Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling gene programs. These transacting mechanisms may explain a portion of the heritable risk for complex vascular diseases. |
Databáze: | MEDLINE |
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