One of the most important questions in regenerative biology is to unveil how and when genes change expression and trigger regeneration programs. The resetting of gene expression patterns during response to injury is governed by coordinated actions of genomic regions that control the activity of multiple sequence-specific DNA binding proteins. Using genome-wide approaches to interrogate chromatin function, we here identify the elements that regulate tissue recovery in Drosophila imaginal discs, which show a high regenerative capacity after genetically induced cell death. Our findings indicate there is global coregulation of gene expression as well as a regeneration program driven by different types of regulatory elements. Novel enhancers acting exclusively within damaged tissue cooperate with enhancers co-opted from other tissues and other developmental stages, as well as with endogenous enhancers that show increased activity after injury. Together, these enhancers host binding sites for regulatory proteins that include a core set of conserved transcription factors that control regeneration across metazoans.

This project was funded by the following grants: PCIN-2013-048 from the Spanish Ministerio de Economía y Competitividad and the Institució Catalana de Recerca i Estudis Avançats (via an ICREA Academia award) to M.C.; BFU2012-36888 and BFU2015-67623-P from the Spanish Ministerio de Economía y Competitividad to F.S. and M.C.; the European Research Council/European Community's Seventh Framework Programme grant 294653 RNA-MAPS, the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Spanish Ministry of Economy and Competitiveness (MEC) “Centro de Excelencia Severo Ochoa,” and the CERCA Programme / Generalitat de Catalunya to R.G.