Changes in regeneration-responsive enhancers shape regenerative capacities in vertebrates

Area of Science:

• Genomics
• Developmental Biology
• Evolutionary Biology

Background:

• Vertebrate regeneration capacity varies significantly.
• The genetic and epigenetic underpinnings of this disparity are not well understood.
• Understanding these mechanisms is key to potentially restoring regenerative abilities.

Purpose of the Study:

• To investigate the genetic and epigenomic factors contributing to differences in vertebrate regeneration.
• To identify conserved and species-specific genomic elements involved in regeneration.
• To explore the role of specific enhancers in regulating regenerative potential.

Main Methods:

• Comparative epigenomic profiling of two related teleost fish species.
• Single-cell sequencing to analyze cellular responses during regeneration.
• Functional assays including enhancer activity testing and genomic deletion in transgenic fish.
• Comparative analysis of enhancer elements between fish and mammals.

Main Results:

• Identified both species-specific and evolutionarily conserved genomic responses to regeneration.
• Discovered several regeneration-responsive enhancers (RREs), including one upstream of the inhibin beta A (inhba) gene.
• Demonstrated that this specific RRE activates gene expression during regeneration and its deletion impairs fin and cardiac regeneration in fish.
• Found homologous enhancers in mammals that respond to injury but cannot restore regeneration, suggesting functional divergence.

Conclusions:

• Changes in AP-1-enriched regeneration-responsive enhancers are strongly implicated in the loss of regenerative capacity across vertebrate evolution.
• The functional divergence of these enhancers between fish and mammals may explain differential regenerative abilities.
• This research provides insights into the genetic basis of regeneration and its evolutionary loss.