ENAGenomicsGarza lab, Dermatology, Johns Hopkins School of Medicinehttps://www.ebi.ac.uk/ena/browser/view/PRJNA688486Mus musculusxref:PubMed:34623736Mammalian injury responses are characterized by fibrosis and scarring rather than the functional regeneration observed in other phyla. Limited regenerative capacity in mammals could reflect a loss of pro-regeneration programs or active suppression by genes functioning akin to tumor suppressors. To uncover programs governing regeneration in mammals, we investigated Wound Induced Hair Neogenesis (WIHN), a rare example of regeneration in adult mammals1,2. Through comprehensive screening of transcripts associated with both WIHN and human facial rejuvenation after laser treatment, we found the endoribonuclease RNase L to be a powerful suppressor of regeneration. Rnasel-/- mice exhibit remarkable regenerative capacity and accelerated wound healing following injury through the production of IL-36α. Consistent with the known role of RNase L to stimulate caspase-1 signaling, we find that pharmacologic inhibition of caspases promotes regeneration in an IL-36-dependent manner. These responses are not limited to skin but occur following intestinal injury as well, suggesting that suppression of regeneration is a general characteristic of mammalian wound healing. Taken together, this work suggests a therapeutic strategy to uncover latent regenerative capacity and promote functional response to injury. Biopsies of re-epithelialized tissue were recovered from wild-type or Rnasel KO mice approximately 10 days after wounding. Total RNA was extracted and sent for microarray analysis. Overall design: Deep tissue wounds of 1.25cm^2 were performed on wild-type or Rnasel KO mice. After 10 days the scab detached (SD0), signifying re-epithelialization. SD0 tissue was surgically removed and total RNA was extracted and submitted for microarray analysis. A single KO sample was compared to a single WT sample.ENAfalseIn vivo gene signature of re-epithelialized tissue post-wounding from wildtype or Rnasel KO miceIn vivo gene signature of re-epithelialized tissue post-wounding from wildtype or Rnasel KO mice2025-09-242021-11-20PRJNA688486GSE1640031009034623736