A reversible epigenetic memory of inflammatory injury controls lineage plasticity and tumor initiation in the mouse pancreas

Dev Cell. 2023 Nov 30:S1534-5807(23)00583-X. doi: 10.1016/j.devcel.2023.11.008. Online ahead of print.ABSTRACTInflammation is essential to the disruption of tissue homeostasis and can destabilize the identity of lineage-committed epithelial cells. Here, we employ lineage-traced mouse models, single-cell transcriptomic and chromatin analyses, and CUT&TAG to identify an epigenetic memory of inflammatory injury in the pancreatic acinar cell compartment. Despite resolution of pancreatitis, our data show that acinar cells fail to return to their molecular baseline, with retention of elevated chromatin accessibility and H3K4me1 at metaplasia genes, such that memory represents an incomplete cell fate decision. In vivo, we find this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second insult but increased tumorigenesis with an oncogenic Kras mutation. The lowered threshold for oncogenic transformation, in turn, can be restored by blockade of MAPK signaling. Together, we define the chromatin dynamics, molecular encoding, and recall of a prolonged epigenetic memory of inflammatory injury that impacts future responses but remains reversible.PMID:38056453 | DOI:10.1016/j.devcel.2023.11.008

Source: Developmental Cell - December 6, 2023 Category: Cytology Authors: David J Falvo Adrien Grimont Paul Zumbo William B Fall Julie L Yang Alexa Osterhoudt Grace Pan Andre F Rendeiro Yinuo Meng John E Wilkinson Friederike D ündar Olivier Elemento Rhonda K Yantiss Erika Hissong Richard Koche Doron Betel Rohit Chandwani Source Type: research