Arid3a regulates nephric tubule regeneration via evolutionarily conserved regeneration signal-response enhancers.

Abstract

Amphibians and fish have the ability to regenerate numerous tissues, whereas mammals have a limited regenerative capacity. Despite numerous developmental genes becoming reactivated during regeneration, an extensive analysis is yet to be performed on whether highly regenerative animals utilize unique <i>cis</i>-regulatory elements for the reactivation of genes during regeneration and how such <i>cis</i>-regulatory elements become activated. Here, we screened regeneration signal-response enhancers at the <i>lhx1</i> locus using <i>Xenopus</i> and found that the noncoding elements conserved from fish to human function as enhancers in the regenerating nephric tubules. A DNA-binding motif of Arid3a, a component of H3K9me3 demethylases, was commonly found in RSREs. Arid3a binds to RSREs and reduces the H3K9me3 levels. It promotes cell cycle progression and causes the outgrowth of nephric tubules, whereas the conditional knockdown of <i>arid3a</i> using photo-morpholino inhibits regeneration. These results suggest that Arid3a contributes to the regeneration of nephric tubules by decreasing H3K9me3 on RSREs.