Epigenetic mechanisms mediate adaptive epithelial-intrinsic resilience to promote intestinal regeneration

• Applicant: Dr. Julian Heuberger
• Subject Area: Gastroenterology ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523078609

The intestinal epithelium is under steady exposure to a harsh digestive environment and represents the first physical defensive barrier against environmental and microbial attacks. Several gastrointestinal bases on defective barrier function and inchoate intestinal regeneration. Different factors reaching from enteropathogens, unbalanced commensal bacteria, metabolites, and lifestyles (e.g. alcohol consumption, diet) can interfere with the epithelial integrity and can be the basis for a spectrum of diseases like cancer and chronic inflammation. A profound understanding of regenerative mechanisms and protective function is essential to develop sufficient treatment strategies for gastrointestinal disease. Fast and regenerative processes ensure the continued protection of the organism after damage of the intestinal epithelium. After epithelial damage, regenerative processes demand re-organization and rebuilding of the tissue architecture and barrier function. The intestinal epithelium demonstrates a high regeneration capacity and the epithelial hierarchy and architecture quickly reconstruct after damage. This regeneration process is enabled by the high plasticity of epithelial cells. Diverse progenitor cells, as well as terminally differentiated epithelial cells, reprogram into stem cells that are required to regenerate and reconstruct the epithelial cell sheet. We have recently demonstrated the role of the epigenetic modifier MLL1 in the control of intestinal cell lineage specification and intestinal cancer stem cell function. However, the role of MLL1 in regeneration remains so far elusive. In the skin, epigenetic regulatory mechanisms are causative for a faster wound healing response to repeated intervention and imply a memory function of epithelia triggered by inflammatory stimuli. Mechanisms of how intestinal epithelial cell plasticity is induced under inflammatory conditions and shift cells from a progenitor state via a regenerative cell state into a stem cell state are not completely understood. Whether epigenetic mechanisms also participate in these processes and preserve or enhance gene responsiveness and impact on intestinal regeneration has not been explored yet. With the support of this proposal, I would like to address the role of the epigenetic modifier MLL1 in regeneration after epithelial injury and in intestinal inflammatory disease, and whether epithelia undergo adaption processes during regeneration. This research project will decipher the role of MLL1 in intestinal regeneration, epigenetic cell reprogramming, and in activating a regenerative program. It will address if intestinal epithelia harbor adaption capabilities and if such epithelial memory is mediated by the epigenetic modifier MLL1, and alters cytokine responsiveness to trigger enhanced regeneration. Furthermore, this study will explore if a causative for patients’ inflammatory colitis is an overshoot of an epithelial-intrinsic adaptation program.

• DFG Programme: Research Grants