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

The paralogous genes Nppa and Nppb are organized in an evolutionary conserved cluster and are a valuable model to study coregulation 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 kbp 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. 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. Overall design: We have used 4C-seq on several viewpoints around the Nppa-Nppb gene cluster in the heart and liver samples to investigate the role of chromatin conformation on regulation of Nppa and Nppb expression during heart development and disease.