Changes in regeneration-responsive enhancers affect regenerative capacities in vertebrates

This topic is within the theme of gene-environment interactions. The “environmental signal” is — loss of a body part. ☹ The “response to that signal” is — let’s mobilize our transcription factors and regulatory elements and activate our genetic networks to make a new body part. 😊

Everyone knows that (if that body part is lost), salamanders can regenerate a tail, and some fish can regenerate a fin. However, mammals (e.g. humans, mice) cannot regenerate a limb. In certain species, the ability to regenerate can be limited only to early developmental stages, and not later in life. Changes in cis-regulatory elements, or enhancers (i.e. short DNA segments usually near to the gene they are regulating) are a major source of morphological diversity. Emerging evidence suggests that activation of injury-dependent gene expression may be controlled by injury-responsive enhancer elements. Two such elements, leptin-b (lepb) enhancer in zebrafish (Danio rerio), and the WNT gene cluster (BRV118) enhancer in fruit flies (Drosophila melanogaster), modulate gene expression after injury. However, ablation of lepb in zebrafish, or ablation of the fly WNT enhancer — does not impede regeneration, suggesting that these injury-responsive components might be necessary but not essential for regeneration. Therefore, whether conserved regeneration-responsive, rather than injury-responsive, elements exist in vertebrate genomes and how they evolve have not been conclusively demonstrated.

Identification of enhancers across species is complicated by the fact that these elements mutate rapidly during evolution. A recent study showed that limb and fin regeneration share a deep evolutionary origin. Thus, authors [see attached article] hypothesized that if genetic mechanisms driving regeneration are evolutionarily conserved in distantly related species (subjected to different selective pressures), then it should be possible to distinguish between species-specific and conserved regeneration-responsive enhancers (RREs).

Robust differences in life history — and the ~230 million years of evolutionary divergence — between zebrafish and African killifish Nothobranchius furzeri provide an exclusive biological context in which to test this hypothesis. Both species can regenerate missing body parts, following amputation; however, whereas zebrafish are found in moderately flowing freshwater habitats in Southern Asia, killifish inhabit temporal ponds subjected to annual desiccation in southeast Africa. Strong selective pressure of seasonal desiccation has driven killifish to evolve interesting features — including rapid sexual maturation (as short as 2 weeks), diapause embryos (delays in embryonic growth), and an extremely short life span (4 to 6 months).

Authors [see attached article] (comparing epigenetic and transcriptional changes during early stages of regeneration), discovered an evolutionarily conserved regeneration program involving the fin and heart. Authors also provide evidence that elements of this program have been subjected to evolutionary changes in vertebrate species (which have limited or no regenerative capacities). Among several conserved regeneration-responsive enhancers (RREs), authors found an element — upstream of inhibin beta A (inhba), which is a known effector of vertebrate regeneration. This element activated expression in regenerating transgenic fish, and its genomic deletion perturbed caudal fin regeneration and blocked cardiac regeneration altogether. This enhancer is present in mammals, shares functionally essential activator protein-1 (AP1)–binding motifs, and responds to injury; however, this mammalian element was unable to rescue regeneration in fish. These data suggest that evolutionary alterations in AP1–enriched RREs are likely a crucial source of the loss of regenerative capacities in vertebrates. 😊 ☹


Science 4 Sept 2020; 369: 1207 eaaz3090

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