TY - JOUR
T1 - Identification of a regulatory domain controlling the Nppa-Nppb gene cluster during heart development and stress
AU - Sergeeva, Irina A.
AU - Hooijkaas, Ingeborg B.
AU - Ruijter, Jan M.
AU - van der Made, Ingeborg
AU - de Groot, Nina E.
AU - van de Werken, Harmen J. G.
AU - Creemers, Esther E.
AU - Christoffels, Vincent M.
PY - 2016
Y1 - 2016
N2 - 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
AB - 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
U2 - https://doi.org/10.1242/dev.132019
DO - https://doi.org/10.1242/dev.132019
M3 - Article
C2 - 27048739
SN - 0950-1991
VL - 143
SP - 2135
EP - 2146
JO - Development (Cambridge, England)
JF - Development (Cambridge, England)
IS - 12
ER -