Identification of a regulatory domain controlling the Nppa-Nppb gene cluster during heart development and stress.

Autor:	Sergeeva IA; Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands., Hooijkaas IB; Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands., Ruijter JM; Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands., van der Made I; Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands., de Groot NE; Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands., van de Werken HJ; Cancer Computational Biology Center, Wytemaweg 80, Erasmus MC Cancer Institute, Erasmus MC, Rotterdam 3015 CN, The Netherlands., Creemers EE; Department of Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands., Christoffels VM; Department of Anatomy, Embryology and Physiology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands v.m.christoffels@amc.uva.nl.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2016 Jun 15; Vol. 143 (12), pp. 2135-46. Date of Electronic Publication: 2016 Apr 05.
DOI:	10.1242/dev.132019
Abstrakt:	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. (© 2016. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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