Scientific Updates

Prof Fuchou Tang’s group profiles DNA methylation and chromatin accessibility of mouse and human fetal germ cells

On 8th Nov, 2016, Prof Fuchou Tang’s group, collaborating with Prof Jie Qiao’s group, online published an article 'DNA methylation and chromatin accessibility profiling of mouse and human fetal germ cells' in Cell Research. This article sysmatically analyzed the dynamic changes of DNA methylation and chromatin accessibility, and their relationship with gene expression, in human and mouse fetal germ cells.

Fetal germ cells (FGCs) are critical for generation transmission. The research team has analyzed DNA methylation reprogramming in human fetal germ cells in 2015 (Guo et al. Cell, 2015). In this study, they applied nucleosome occupancy and methylation sequencing (NOMe-seq), which is able to profile chromatin accessibility and DNA methylation together for a limited number of cells, to human and mouse early fetal germ cells. They also applied RNA-seq for analyzing the relationship between epigenome and transcriptome. In the study, first, the researchers identified 116,887 and 137,557 nucleosome-depleted regions (NDRs) in human and mouse FGCs, respectively. Among these, 84,834 in human and 109,264 in mouse were distal NDRs, which were distant from the transcription starting sitec and were candiates for enhancers. Second, these distal NDRs strongly enriched binding motifs of pluripotency-specific or early germ cell-specific transcription factors such as OCT4, NANOG and SOX17 in human, and Oct4, Nanog and Sox2 in mouse. This suggests that these transcription factors play crucial roles in initiating and maintaining open chromatin states for somatic cell-specific genes and consequently impact on gonadal somatic cell development. Particularlly, SOX17 and SOX2 are highly expressed in early human and mouse PGCs and are important for their development, respectively, reflecting species difference. Third, the authors found that SINE/variable number of tandem repeats/Alu elements (SVAs), which are abundant in primate but not mouse, have significantly higher accessibility than SINEs, LINEs and long-terminal repeats (LTRs) human germline. SVAs also have the most abundant transcripts in human FGCs compared with neighboring somatic cells. Fourth, consistent with previous reports of the team, the authors found that the evolutionarily younger subfamilies, L1 and Alu, tend to have more active transcription activities than the evolutionarily older ones, and also retain higher levels of residual DNA methylation than the older ones after the global DNA demethylation in human and mouse FGCs (Guo et al. Nature, 2014; Guo et al. Cell, 2015). In this study, the authors further found that evolutionarily younger L1 is less open than older L2, and evolutionarily younger Alu is less accessible than older MIR in human FGCs; they also keep more DNA methylation, suggesting low chromatin accessbility and high DNA methylation together repress the transcription and transposition of these evolutionarily younger transposons.

Figure 1. Chromatin accessibility of the distal regulatory elements in mammalian germline.


Dr Hongshan Guo and Dr Boqiang Hu in BIOPIC, and Dr Liying Yan and Dr Jun Yong in Reproductive Medicine Center of Peking Universtiy Third Hospital are co-first authors; Prof Fuchou Tang and Prof Jie Qiao are co-corresponding authors. This project are supported by grants from the National Natural Science Foundation of China, the National Basic Research Program of China and Beijing Advanced Innovation Center for Genomics at Peking University.


Figure 2. Sketch of reprogramming dynamics of endogenous DNA methylation, chromatin accessibility, as well as gene expression patterns during mouse and human germ cell development.