Academic Journal
FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells
| العنوان: | FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells |
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| المؤلفون: | Wong, Doris, Auguste, Gaelle, Lino Cardenas, Christian L., Turner, Adam W., Chen, Yixuan, Song, Yipei, Ma, Lijiang, Perry, R. Noah, Aherrahrou, Redouane, Kuppusamy, Maniselvan, Yang, Chaojie, Mosquera, Jose Verdezoto, Dube, Collin J., Khan, Mohammad Daud, Palmore, Meredith, Kalra, Jaspreet, Kavousi, Maryam, Peyser, Patricia A., Matic, Ljubica, Hedin, Ulf, Manichaikul, Ani, Sonkusare, Swapnil K., Civelek, Mete, Kovacic, Jason C., Bjorkegren, Johan L.M., Malhotra, Rajeev, Miller, Clint L. |
| المصدر: | Wong , D , Auguste , G , Lino Cardenas , C L , Turner , A W , Chen , Y , Song , Y , Ma , L , Perry , R N , Aherrahrou , R , Kuppusamy , M , Yang , C , Mosquera , J V , Dube , C J , Khan , M D , Palmore , M , Kalra , J , Kavousi , M , Peyser , P A , Matic , L , Hedin , U , Manichaikul , A , Sonkusare , S K , Civelek , .... |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, name=SDG 3 - Good Health and Well-being |
| الوصف: | 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | https://pure.eur.nl/en/publications/413b2516-0bd2-4951-b8ff-497d1c42fe5f |
| DOI: | 10.1161/circresaha.122.321692 |
| الاتاحة: | https://pure.eur.nl/en/publications/413b2516-0bd2-4951-b8ff-497d1c42fe5f https://doi.org/10.1161/circresaha.122.321692 http://www.scopus.com/inward/record.url?scp=85157984094&partnerID=8YFLogxK |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.3FC1F89F |
| قاعدة البيانات: | BASE |
| DOI: | 10.1161/circresaha.122.321692 |
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