Broad Heterochromatic Domains Open in Gonocyte Development Prior to De Novo DNA Methylation

Dev Cell. 2019 Oct 7;51(1):21-34.e5. doi: 10.1016/j.devcel.2019.07.023. | PubMed

Soichiro Yamanaka¹, Hidenori Nishihara², Hidehiro Toh³, Luis Augusto Eijy Nagai⁴, Kosuke Hashimoto⁵, Sung-Joon Park⁴, Aoi Shibuya¹, Ana Maria Suzuki⁵, Yujiro Tanaka¹, Kenta Nakai⁴, Piero Carninci⁵, Hiroyuki Sasaki³, Haruhiko Siomi⁶

1. Department of Molecular Biology, Keio University School of Medicine, Tokyo 160-8582, Japan.
2. Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
3. Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
4. Human Genome Center, The Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan.
5. Division of Genomic Technologies, RIKEN Center for Life Science Technologies, RIKEN Yokohama Campus, Kanagawa 230-0045, Japan.
6. Department of Molecular Biology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: awa403@keio.jp.

Abstract

Facultative heterochromatin forms and reorganizes in response to external stimuli. However, how the initial establishment of such a chromatin state is regulated in cell-cycle-arrested cells remains unexplored. Mouse gonocytes are arrested male germ cells, at which stage the genome-wide DNA methylome forms. Here, we discovered transiently accessible heterochromatin domains of several megabases in size in gonocytes and named them differentially accessible domains (DADs). Open DADs formed in gene desert and gene cluster regions, primarily at transposons, with the reprogramming of histone marks, suggesting DADs as facultative heterochromatin. De novo DNA methylation took place with two waves in gonocytes: the first region specific and the second genome-wide. DADs were resistant to the first wave and their opening preceded the second wave. In addition, the higher-order chromosome architecture was reorganized with less defined chromosome compartments in gonocytes. These findings suggest that multiple layers of chromatin reprogramming facilitate de novo DNA methylation.

Presented By Soichiro Yamanaka