Methylomic trajectories in the developing human pancreas

Epigenetic processes such as DNA methylation play a key role in regulating tissue-specific and temporally-appropriate patterns of gene expression during development. Our knowledge about temporal changes to the epigenome in the developing human pancreas is limited. In this study we quantified levels of DNA methylation at over 800,000 sites in 112 human fetal pancreatic samples (51 male and 61 female) spanning from 6 to 21 post conception weeks (pcw). We found dramatic changes in DNA methylation across human pancreas development, with >22% of all methylation sites displaying significant changes across developmental age, with the majority of these sites showing stable levels of DNA methylation in the mature pancreas. Sites associated with developmental changes in DNA methylation during fetal pancreas development were significantly underrepresented in promoter regulatory regions but significantly overrepresented in regions flanking CpG islands (shores and shelves) and gene bodies. Highly significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small number of regions showing sex-specific DNA methylation trajectories across pancreas development. Weighted gene correlation network analysis (WGCNA) revealed modules of co-methylated loci associated with developmental age were enriched for genes involved in maturity onset diabetes of the young (MODY) and other metabolic phenotypes. A comparison with developmentally-dynamic patterns of DNA methylation in the developing human brain revealed significant tissue specific differences between the fetal pancreas and the fetal brain. Our data confirms the prenatal period to be a time of dynamic epigenetic changes. To our knowledge, this is the most extensive study of DNA methylation patterns in human fetal pancreatic development. Quantified DNA methylation across the genome in 99 human fetal and 23 human adult pancreas samples