Rewiring of the epigenome and chromatin architecture by retinoic acid signaling during zebrafish embryonic development

Abstract

BackgroundRetinoic acid (RA) functions as a ligand for the nuclear RA receptors (RARs), which regulate the expression of target genes by binding to RA response elements. RA signaling is required for multiple processes during chordate embryonic development, such as body axis extension, hindbrain antero-posterior patterning and forelimb bud initiation. Although some RA target genes have been identified, little is known about the genome-wide effects of RA signaling during in vivo embryonic development. ResultsHere we stimulate the RA pathway during development by treating zebrafish embryos with all-trans-RA (atRA), the most abundant form of RA, and use a combination of RNA-seq, ATAC-seq, ChIP-seq and HiChIP to gain insight into the molecular mechanisms by which RA signaling control target gene expression. We find that RA signaling is involved in anterior/posterior patterning and development of the central nervous system, participating in the transition from pluripotency to differentiation. atRA treatment also induces alterations in chromatin accessibility during early development and promotes chromatin binding of RARa and the RA targets Hoxb1b, Meis2b and Sox3, which cooperate in central nervous system development. Finally, we show that RA induces a rewiring of chromatin architecture, with alterations in chromatin 3D interactions that are consistent with target gene expression. This is illustrated by the specific induction of anterior HoxB genes by RARs, among other examples. ConclusionsAltogether, our findings identify genome-wide targets of RA signaling during embryonic development and provide a molecular mechanism by which developmental signaling pathways regulate the expression of target genes by altering chromatin topology.