FHL5 Controls Vascular Disease–Associated Gene Programs in Smooth Muscle Cells
Rattachement africain : us, de, fi, nl, se, au. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
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.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- FHL5 Controls Vascular Disease–Associated Gene Programs in Smooth Muscle Cells
- Date Crossref
- 28/04/2023
- Éditeur
- Ovid Technologies (Wolters Kluwer Health)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
University of Virginia C.L.M.) pays non établi dans la noticeUniversité ou école supérieure
-
Massachusetts General Hospital pays non établi dans la noticeÉtablissement de santé
-
Icahn School of Medicine at Mount Sinai Department of Genetics and Genomic Sciences pays non établi dans la noticeUniversité ou école supérieure
-
Universität Hamburg pays non établi dans la noticeUniversité ou école supérieure
-
University of Eastern Finland Virtanen Institute for Molecular Sciences pays non établi dans la noticeUniversité ou école supérieure
-
Finland University pays non établi dans la noticeUniversité ou école supérieure
-
University Medical Center Hamburg-Eppendorf pays non établi dans la noticeÉtablissement de santé
-
German Centre for Cardiovascular Research pays non établi dans la noticeStructure de recherche
-
University of Lübeck pays non établi dans la noticeUniversité ou école supérieure
-
Erasmus MC pays non établi dans la noticeÉtablissement de santé
-
University of Michigan pays non établi dans la noticeUniversité ou école supérieure
-
Karolinska Institutet pays non établi dans la noticeUniversité ou école supérieure
C.L.M.) — University of Virginia, Massachusetts General Hospital et Department of Genetics and Genomic Sciences — Icahn School of Medicine at Mount Sinai, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.