Epigenetic reprogramming in Mist1(-/-) mice predicts the molecular response to cerulein-induced pancreatitis.
Gene expression is affected by modifications to histone core proteins within chromatin. Changes in these modifications, or epigenetic reprogramming, can dictate cell fate and promote susceptibility to disease. The goal of this study was to determine the extent of epigenetic reprogramming in response to chronic stress that occurs following ablation of MIST1 (Mist1(-/-) ), which is repressed in pancreatic disease. Chromatin immunoprecipitation for trimethylation of lysine residue 4 on histone 3 (H3K4Me3) in purified acinar cells from wild type and Mist1(-/-) mice was followed by Next Generation sequencing (ChIP-seq) or ChIP-qPCR. H3K4Me3-enriched genes were assessed for expression by qRT-PCR in pancreatic tissue before and after induction of cerulein-induced pancreatitis. While most of H3K4Me3-enrichment is restricted to transcriptional start sites, >25% of enrichment sites are found within, downstream or between annotated genes. Less than 10% of these sites were altered in Mist1(-/-) acini, with most changes in H3K4Me3 enrichment not reflecting altered gene expression. Ingenuity Pathway Analysis of genes differentially-enriched for H3K4Me3 revealed an association with pancreatitis and pancreatic ductal adenocarcinoma in Mist1(-/-) tissue. Most of these genes were not differentially expressed but several were readily induced by acute experimental pancreatitis, with significantly increased expression in Mist1(-/-) tissue relative to wild type mice. We suggest that the chronic cell stress observed in the absence of MIST1 results in epigenetic reprogramming of genes involved in promoting pancreatitis to a poised state, thereby increasing the sensitivity to events that promote disease.
Children's Health Research Institute, London, Ontario, Canada ; Children's Health Research Institute, Department of Paediatrics, London, Ontario, Canada.
Rashid
R
Mehmood
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
Gabor
G
Varga
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
Sonali Q
SQ
Mohanty
Children's Health Research Institute, London, Ontario, Canada ; Children's Health Research Institute, Department of Paediatrics, London, Ontario, Canada ; Children's Health Research Institute, Department of Physiology & Pharmacology, London, Ontario, Canada.
Scott W
SW
Laing
Biostatistics and Programming, Sanofi US, Framingham, Massachusetts, United States of America.
Yuefeng
Y
Lu
Children's Health Research Institute, London, Ontario, Canada ; Children's Health Research Institute, Department of Paediatrics, London, Ontario, Canada.
Charis L
CL
Johnson
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America.
Alexei
A
Kharitonenkov
Children's Health Research Institute, London, Ontario, Canada ; Children's Health Research Institute, Department of Paediatrics, London, Ontario, Canada ; Children's Health Research Institute, Department of Physiology & Pharmacology, London, Ontario, Canada ; Oncology, the University of Western Ontario, London, Ontario, Canada.
Christopher L
CL
Pin
D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002108:Ceruletide; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D051792:Basic Helix-Loop-Helix Proteins; D002108:Ceruletide; D002843:Chromatin; D006657:Histones; C491312:Bhlha15 protein, mouse