Changes in regeneration-responsive enhancers shape regenerative capacities in vertebrates

• Published in: Science (American Association for the Advancement of Science) Vol. 369; no. 6508
• Main Authors: Wang, Wei, Hu, Chi-Kuo, Zeng, An, Alegre, Dana, Hu, Deqing, Gotting, Kirsten, Ortega Granillo, Augusto, Wang, Yongfu, Robb, Sofia, Schnittker, Robert, Zhang, Shasha, Alegre, Dillon, Li, Hua, Ross, Eric, Zhang, Ning, Brunet, Anne, Sánchez Alvarado, Alejandro
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 04.09.2020
• Subjects: Ablation; Activator protein 1; Amino Acid Motifs; Amputation; Animals; Appendages; Binding; Biological evolution; Chromatin; Context; Danio rerio; Deletion; Enhancer Elements, Genetic - physiology; Enhancers; Epigenesis, Genetic; Evolution; Evolution, Molecular; Feedback (Response); Fish; Fruit flies; Functional testing; Gene expression; Gene Expression Profiling; Gene sequencing; Genetics; Genomes; Genomics; Heart; Histones - metabolism; Immunoprecipitation; Inhibin; Inhibin-beta Subunits - genetics; Injuries; Killifishes - genetics; Killifishes - physiology; Life history; Mammals; Molecular modelling; Organs; Phylogeny; Physical Disabilities; Proteins; Regeneration; Regeneration - genetics; Regenerators; Regulatory sequences; Ribonucleic acid; RNA; RNA-Seq; Single-Cell Analysis; Speciation; Species; Spinal cord; Transcription Factor AP-1 - chemistry; Transcription Factor AP-1 - metabolism; Transcription factors; Transcriptional Activation; Transgenic fish; Vertebrates; Zebrafish; Zebrafish - genetics; Zebrafish - physiology
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aaz3090

Some animals regenerate extensively, whereas others, such as mammals, do not. The reason behind this difference is not clear. If the genetic mechanisms driving regeneration are evolutionarily conserved, the study of distantly related species that are subjected to different selective pressures could identify distinguishing species-specific and conserved regeneration-responsive mechanisms. Zebrafish and the short-lived African killifish are separated by ∼230 million years of evolutionary distance and, as such, provide a biological context to elucidate molecular mechanisms. Wang et al. identify both species-specific and evolutionarily conserved regeneration programs in these fish. They also provide evidence that elements of this program are subjected to evolutionary changes in vertebrate species with limited or no regenerative capacities. Science , this issue p. eaaz3090 Comparison of two related but evolutionarily distant fish species reveals regulatory elements involved in tissue regeneration. Vertebrates vary in their ability to regenerate, and the genetic mechanisms underlying such disparity remain elusive. Comparative epigenomic profiling and single-cell sequencing of two related teleost fish uncovered species-specific and evolutionarily conserved genomic responses to regeneration. The conserved response revealed several regeneration-responsive enhancers (RREs), including an element upstream to inhibin beta A ( inhba ), a known effector of vertebrate regeneration. This element activated expression in regenerating transgenic fish, and its genomic deletion perturbed caudal fin regeneration and abrogated cardiac regeneration altogether. The enhancer is present in mammals, shares functionally essential activator protein 1 (AP-1)–binding motifs, and responds to injury, but it cannot rescue regeneration in fish. This work suggests that changes in AP-1–enriched RREs are likely a crucial source of loss of regenerative capacities in vertebrates.