title: Identification of a regulatory domain controlling the Nppa-Nppb gene cluster during heart development and stress.
abstract: The paralogous genes Nppa and Nppb are organized in an evolutionarily conserved cluster and provide a valuable model for studying co-regulation and regulatory landscape organization during heart development and disease. Here, we analyzed the chromatin conformation, epigenetic status and enhancer potential of sequences of the Nppa-Nppb cluster in vivo Our data indicate that the regulatory landscape of the cluster is present within a 60-kb domain centered around Nppb Both promoters and several potential regulatory elements interact with each other in a similar manner in different tissues and developmental stages. The distribution of H3K27ac and the association of Pol2 across the locus changed during cardiac hypertrophy, revealing their potential involvement in stress-mediated gene regulation. Functional analysis of double-reporter transgenic mice revealed that Nppa and Nppb share developmental, but not stress-response, enhancers, responsible for their co-regulation. Moreover, the Nppb promoter was required, but not sufficient, for hypertrophy-induced Nppa expression. In summary, the developmental regulation and stress response of the Nppa-Nppb cluster involve the concerted action of multiple enhancers and epigenetic changes distributed across a structurally rigid regulatory domain.
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Sergeeva
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Ingeborg B
authors.initials: IB
authors.lastname: Hooijkaas
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Ruijter
authors.affiliation: Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: van der Made
authors.affiliation: Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Nina E
authors.initials: NE
authors.lastname: de Groot
authors.affiliation: Cancer Computational Biology Center, Wytemaweg 80, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam 3015 CN, The Netherlands.
authors.forename: Harmen J G
authors.initials: HJ
authors.lastname: van de Werken
authors.affiliation: Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Creemers
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands v.m.christoffels@amc.uva.nl.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
mesh_terms: D000107:Acetylation; D000818:Animals; D009320:Atrial Natriuretic Factor; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D006321:Heart / Q000196:embryology*; D006657:Histones / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D005810:Multigene Family; D020098:Natriuretic Peptide, C-Type / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics*; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D009320:Atrial Natriuretic Factor; D006657:Histones; D008239:Lysine; D020098:Natriuretic Peptide, C-Type; D011498:Protein Precursors; D012319:RNA Polymerase II; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B; C431578:Nppa protein, mouse
keywords: Atrial and brain natriuretic peptide; Chromosome conformation; Epigenetics; Heart development; Hypertrophy; Mouse