دورية أكاديمية
أعرض في EDS

Genetic Dissection of a Super Enhancer Controlling the Nppa-Nppb Cluster in the Heart.

التفاصيل البيبلوغرافية
العنوان: Genetic Dissection of a Super Enhancer Controlling the Nppa-Nppb Cluster in the Heart.
المؤلفون: Man JCK; Department of Medical Biology (J.C.K.M., K.v.D., I.B.H., C.d.G.-d.V., V.W., B.J.B., V.M.C.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands., van Duijvenboden K; Department of Medical Biology (J.C.K.M., K.v.D., I.B.H., C.d.G.-d.V., V.W., B.J.B., V.M.C.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands., Krijger PHL; Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, the Netherlands (P.H.L.K., W.d.L.)., Hooijkaas IB; Department of Medical Biology (J.C.K.M., K.v.D., I.B.H., C.d.G.-d.V., V.W., B.J.B., V.M.C.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands., van der Made I; Department of Experimental Cardiology (I.v.d.M., E.E.C., B.J.B.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands., de Gier-de Vries C; Department of Medical Biology (J.C.K.M., K.v.D., I.B.H., C.d.G.-d.V., V.W., B.J.B., V.M.C.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands., Wakker V; Department of Medical Biology (J.C.K.M., K.v.D., I.B.H., C.d.G.-d.V., V.W., B.J.B., V.M.C.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands., Creemers EE; Department of Experimental Cardiology (I.v.d.M., E.E.C., B.J.B.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands., de Laat W; Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, the Netherlands (P.H.L.K., W.d.L.)., Boukens BJ; Department of Medical Biology (J.C.K.M., K.v.D., I.B.H., C.d.G.-d.V., V.W., B.J.B., V.M.C.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.; Department of Experimental Cardiology (I.v.d.M., E.E.C., B.J.B.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands., Christoffels VM; Department of Medical Biology (J.C.K.M., K.v.D., I.B.H., C.d.G.-d.V., V.W., B.J.B., V.M.C.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, location AMC, The Netherlands.
المصدر: Circulation research [Circ Res] 2021 Jan 08; Vol. 128 (1), pp. 115-129. Date of Electronic Publication: 2020 Oct 27.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Baltimore, MD : Lippincott Williams & Wilkins
Original Publication: Baltimore, Md. Grune & Stratton.
مواضيع طبية MeSH: Enhancer Elements, Genetic* , Multigene Family*, Atrial Natriuretic Factor/*genetics , Hypertrophy, Left Ventricular/*genetics , Myocardial Infarction/*genetics , Myocytes, Cardiac/*metabolism , Natriuretic Peptide, Brain/*genetics, Animals ; Atrial Natriuretic Factor/metabolism ; Binding Sites ; Binding, Competitive ; CRISPR-Cas Systems ; Cell Line ; Disease Models, Animal ; Epigenesis, Genetic ; Gene Expression Regulation, Developmental ; Humans ; Hypertrophy, Left Ventricular/metabolism ; Hypertrophy, Left Ventricular/pathology ; Mice, Knockout ; Myocardial Infarction/metabolism ; Myocardial Infarction/pathology ; Myocytes, Cardiac/pathology ; Natriuretic Peptide, Brain/metabolism ; Promoter Regions, Genetic ; Mice
مستخلص: Rationale: ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide), encoded by the clustered genes Nppa and Nppb , are important prognostic, diagnostic, and therapeutic proteins in cardiac disease. The spatiotemporal expression pattern and stress-induction of the Nppa and Nppb are tightly regulated, possibly involving their coregulation by an evolutionary conserved enhancer cluster.
Objective: To explore the physiological functions of the enhancer cluster and elucidate the genomic mechanism underlying Nppa-Nppb coregulation in vivo.
Methods and Results: By analyzing epigenetic data we uncovered an enhancer cluster with super enhancer characteristics upstream of Nppb . Using CRISPR/Cas9 genome editing, the enhancer cluster or parts thereof, Nppb and flanking regions or the entire genomic block spanning Nppa-Nppb , respectively, were deleted from the mouse genome. The impact on gene regulation and phenotype of the respective mouse lines was investigated by transcriptomic, epigenomic, and phenotypic analyses. The enhancer cluster was essential for prenatal and postnatal ventricular expression of Nppa and Nppb but not of any other gene. Enhancer cluster-deficient mice showed enlarged hearts before and after birth, similar to Nppa-Nppb compound knockout mice we generated. Analysis of the other deletion alleles indicated the enhancer cluster engages the promoters of Nppa and Nppb in a competitive rather than a cooperative mode, resulting in increased Nppa expression when Nppb and flanking sequences were deleted. The enhancer cluster maintained its active epigenetic state and selectivity when its target genes are absent. In enhancer cluster-deficient animals, Nppa was induced but remained low in the postmyocardial infarction border zone and in the hypertrophic ventricle, involving regulatory sequences proximal to Nppa .
Conclusions: Coordinated ventricular expression of Nppa and Nppb is controlled in a competitive manner by a shared super enhancer, which is also required to augment stress-induced expression and to prevent premature hypertrophy.
التعليقات: Comment in: Circ Res. 2021 Jan 8;128(1):130-132. (PMID: 33411631)
فهرسة مساهمة: Keywords: epigenomics; gene expression regulation; myocardium; natriuretic peptides; regulatory elements, transcriptional
المشرفين على المادة: 0 (NPPA protein, human)
0 (Nppa protein, mouse)
114471-18-0 (Natriuretic Peptide, Brain)
85637-73-6 (Atrial Natriuretic Factor)
تواريخ الأحداث: Date Created: 20201027 Date Completed: 20210726 Latest Revision: 20240226
رمز التحديث: 20240226
DOI: 10.1161/CIRCRESAHA.120.317045
PMID: 33107387
قاعدة البيانات: MEDLINE
الوصف
تدمد:1524-4571
DOI:10.1161/CIRCRESAHA.120.317045