Resolving Heart Regeneration by Replacement Histone Profiling

Chromatin regulation is a principal mechanism governing animal development, yet it is unclear to what extent structural changes in chromatin underlie tissue regeneration. Non-mammalian vertebrates such as zebrafish activate cardiomyocyte (CM) division after tissue damage to regenerate lost heart muscle. Here, we generated transgenic zebrafish expressing a biotinylatable H3.3 histone variant in CMs and derived cell-type-specific profiles of histone replacement. We identified an emerging program of putative enhancers that revise H3.3 occupancy during regeneration, overlaid upon a genome-wide reduction of H3.3 from promoters. In transgenic reporter lines, H3.3-enriched elements directed gene expression in subpopulations of CMs. Other elements increased H3.3 enrichment and displayed enhancer activity in settings of injury- and/or Neuregulin1-elicited CM proliferation. Dozens of consensus sequence motifs containing predicted transcription factor binding sites were enriched in genomic regions with regeneration-responsive H3.3 occupancy. Thus, cell-type-specific regulatory programs of tissue regeneration can be revealed by genome-wide H3.3 profiling. [Display omitted] •A transgenic reagent for profiling histone H3.3 occupancy in cardiomyocytes•Identification of regulatory elements directing gene expression in cardiomyocytes•Elucidation of enhancer elements preferential to heart regeneration•Discovery of sequence motifs in H3.3-enriched genomic regions during regeneration Cell-type-specific chromatin profiling can shed light on intrinsic genetic programs, but such analysis in regenerating tissues has technical challenges. Goldman, Kuzu et al. develop transgenic zebrafish enabling cardiomyocyte-specific histone H3.3 profiling to capture sites of nucleosome turnover. They identify regulatory elements preferential for heart regeneration during the dynamic process.