DNA methylation dynamics and dysregulation delineated by high-throughput profiling in the mouse
Wanding Zhou, Toshinori Hinoue, Bret Barnes, Owen Mitchell, Waleed Iqbal, Sol Moe Lee, Kelly K. Foy, Kwang‐Ho Lee, Ethan Jacob Moyer, Alexandra VanderArk, Julie Koeman, Wubin Ding, Manpreet Kalkat, Nathan J. Spix, Bryn Eagleson, J. Andrew Pospisilik, Piroska E. Szabó, Marisa S. Bartolomei, Nicole A. Vander Schaaf, Liang Kang, Ashley K. Wiseman, Peter A. Jones, Connie M. Krawczyk, Marie Adams, Rishi Porecha, Brian H. Chen, Hui Shen, Peter W. Laird
Abstract
We have developed a mouse DNA methylation array that contains 296,070 probes representing the diversity of mouse DNA methylation biology. We present a mouse methylation atlas as a rich reference resource of 1,239 DNA samples encompassing distinct tissues, strains, ages, sexes, and pathologies. We describe applications for comparative epigenomics, genomic imprinting, epigenetic inhibitors, patient-derived xenograft assessment, backcross tracing, and epigenetic clocks. We dissect DNA methylation processes associated with differentiation, aging, and tumorigenesis. Notably, we find that tissue-specific methylation signatures localize to binding sites for transcription factors controlling the corresponding tissue development. Age-associated hypermethylation is enriched at regions of Polycomb repression, while hypomethylation is enhanced at regions bound by cohesin complex members. ApcMin/+ polyp-associated hypermethylation affects enhancers regulating intestinal differentiation, while hypomethylation targets AP-1 binding sites. This Infinium Mouse Methylation BeadChip (version MM285) is widely accessible to the research community and will accelerate high-sample-throughput studies in this important model organism.