Defining the molecular determinants of inflammatory memory in the pancreas

Project Summary / Abstract Biological systems operate within fluctuating environments, and, therefore, are inherently tasked with accurately responding in real-time to a myriad of signals. Recent evidence suggests that a memory of inflammation can be encoded and retained in the epigenome of cells even following resolution of the initial stimulus. The presence of `inflammatory memory' suggests that preservation of tissue homeostasis also incorporates an evolutionary adaptation in which future responses are educated by past experiences. Inflammation is essential to the disruption of tissue homeostasis, and, in the pancreas, can destabilize the identity of terminally differentiated acinar cells. Recently, we have employed lineage-traced mouse models to delineate the chromatin dynamics that accompany the cycle of metaplasia and regeneration following pancreatitis, and unveiled the presence of an epigenetic memory of inflammation in the pancreatic acinar cell compartment. We have observed that despite histologic resolution of pancreatitis, acinar cells fail to return to their molecular baseline after several months, representing an incomplete cell fate decision – one wherein there is persistent MAPK signaling, AP-1 activation, and IL-33 in the pancreas microenvironment. In vivo, this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second inflammatory insult but increased tumorigenesis with an oncogenic Kras mutation. We have demonstrated that both persistent chromatin and transcriptional changes constituting memory can be specifically recalled in the response to oncogenic stress. Together, our findings have defined the dynamics and recall of an epigenetic memory of inflammation that impacts cell fate decisions. In this proposal, we focus on building an understanding of the molecular underpinnings of memory of inflammation. Specifically, we will leverage our lineage-traced mouse models of pancreatic inflammation to establish an understanding of AP-1 binding to chromatin and its interaction partners (Aim 1). We will also employ specific genetic and pharmacologic perturbations to AP-1 factors and MAPK signaling in vivo to articulate whether epigenetic memory is reversible (i.e. inducing epigenetic `amnesia') (Aim 2). Third, we will examine the role of IL-33 as a cell-extrinsic factor driving the memory phenotype (Aim 3). Together our studies will define the molecular mechanisms that govern epigenetic memory of inflammation in the pancreas. In so doing, we expect to uncover the key cell types, transcription factors, and signaling intermediates that lead to persistent molecular alterations following transient injury. In turn, this work will shed new light in to how memory can be targeted to abrogate the diminished threshold for tumorigenesis. By analyzing the rational means for inducing epigenetic `amnesia', we will exploit the therapeutic opportunity that the durability of epigenetic memory offers to address the lasting implications of an inflammatory insult.