Global Landscape and Regulatory Principles of DNA Methylation Reprogramming for Germ Cell Specification by Mouse Pluripotent Stem Cells

• DOI: 10.1016/j.devcel.2016.08.008
• Publication Date: 2016-09-16T03:30:50Z
• Authors: Kenjiro Shirane; Kazuki Kurimoto; Yukihiro Yabuta; Masashi Yamaji; Junko Satoh; Shinji Ito; Akira Watanabe; Katsuhiko Hayashi; Mitinori Saitou; Hiroyuki Sasaki
• Keywords: Pluripotent Stem Cells; 0301 basic medicine; Transcription, Genetic; Gene Expression Regulation, Developmental; RNA-Binding Proteins; Mouse Embryonic Stem Cells; DNA Methylation; Cellular Reprogramming; DNA-Binding Proteins; Histones; Mice; 03 medical and health sciences; Enhancer Elements, Genetic; Germ Cells; Metabolome; Animals; Female; Germ Layers; Transcription Factors

Specification of primordial germ cells (PGCs) activates epigenetic reprogramming for totipotency, the elucidation of which remains a fundamental challenge. Here, we uncover regulatory principles for DNA methylation reprogramming during in vitro PGC specification, in which mouse embryonic stem cells (ESCs) are induced into epiblast-like cells (EpiLCs) and then PGC-like cells (PGCLCs). While ESCs reorganize their methylome to form EpiLCs, PGCLCs essentially dilute the EpiLC methylome at constant, yet different, rates between unique sequence regions and repeats. ESCs form hypomethylated domains around pluripotency regulators for their activation, whereas PGCLCs create demethylation-sensitive domains around developmental regulators by accumulating abundant H3K27me3 for their repression. Loss of PRDM14 globally upregulates methylation and diminishes the hypomethylated domains, but it preserves demethylation-sensitive domains. Notably, female ESCs form hypomethylated lamina-associated domains, while female PGCLCs effectively reverse such states into a more normal configuration. Our findings illuminate the unique orchestration of DNA methylation and histone modification reprogramming during PGC specification.