Quantitative Dynamics of Chromatin Remodeling during Germ Cell Specification from Mouse Embryonic Stem Cells

• Published in: Cell stem cell Vol. 16; no. 5; pp. 517 - 532
• Main Authors: Kurimoto, Kazuki, Yabuta, Yukihiro, Hayashi, Katsuhiko, Ohta, Hiroshi, Kiyonari, Hiroshi, Mitani, Tadahiro, Moritoki, Yoshinobu, Kohri, Kenjiro, Kimura, Hiroshi, Yamamoto, Takuya, Katou, Yuki, Shirahige, Katsuhiko, Saitou, Mitinori
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.05.2015
• Subjects: Animals; Cell Differentiation; Cells, Cultured; Chromatin Assembly and Disassembly; Embryonic Germ Cells - physiology; Embryonic Stem Cells - physiology; Epigenesis, Genetic; Epigenetic Repression; Epigenomics; Fetal Proteins - genetics; Fetal Proteins - metabolism; Histones - genetics; Histones - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Methylation; Mice; Positive Regulatory Domain I-Binding Factor 1; Protein Binding; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2015.03.002

Germ cell specification is accompanied by epigenetic remodeling, the scale and specificity of which are unclear. Here, we quantitatively delineate chromatin dynamics during induction of mouse embryonic stem cells (ESCs) to epiblast-like cells (EpiLCs) and from there into primordial germ cell-like cells (PGCLCs), revealing large-scale reorganization of chromatin signatures including H3K27me3 and H3K9me2 patterns. EpiLCs contain abundant bivalent gene promoters characterized by low H3K27me3, indicating a state primed for differentiation. PGCLCs initially lose H3K4me3 from many bivalent genes but subsequently regain this mark with concomitant upregulation of H3K27me3, particularly at developmental regulatory genes. PGCLCs progressively lose H3K9me2, including at lamina-associated perinuclear heterochromatin, resulting in changes in nuclear architecture. T recruits H3K27ac to activate BLIMP1 and early mesodermal programs during PGCLC specification, which is followed by BLIMP1-mediated repression of a broad range of targets, possibly through recruitment and spreading of H3K27me3. These findings provide a foundation for reconstructing regulatory networks of the germline epigenome. [Display omitted] •Chromatin dynamics were quantitatively assessed during PCG specification•EpiLCs represent a primed state with abundant bivalency with low H3K27me3•PGCLCs deplete H3K9me2 throughout the genome including from lamina-associated domains•BLIMP1 serves as a potential nucleator for H3K27me3 accumulation and spread Kurimoto et al. perform careful analyses of chromatin remodeling during mouse germ cell specification from embryonic stem cells. Widespread epigenetic reprogramming events included re-organization of H3K27me3 and bivalent signatures as well as progressive deletion of H3K9me2 throughout the genome, creating a unique foundation for the epigenome of the next generation.