Abstract
Chromatin remodeling is important for the epigenetic reprogramming of human primordial germ cells. However, the comprehensive chromatin state has not yet been analyzed for human fetal germ cells (FGCs). Here we use nucleosome occupancy and methylation sequencing method to analyze both the genome-wide chromatin accessibility and DNA methylome at a series of crucial time points during fetal germ cell development in both human and mouse. We find 116 887 and 137 557 nucleosome-depleted regions (NDRs) in human and mouse FGCs, covering a large set of germline-specific and highly dynamic regulatory genomic elements, such as enhancers. Moreover, we find that the distal NDRs are enriched specifically for binding motifs of the pluripotency and germ cell master regulators such as NANOG, SOX17, AP2γ and OCT4 in human FGCs, indicating the existence of a delicate regulatory balance between pluripotency-related genes and germ cell-specific genes in human FGCs, and the functional significance of these genes for germ cell development in vivo. Our work offers a comprehensive and high-resolution roadmap for dissecting chromatin state transition dynamics during the epigenomic reprogramming of human and mouse FGCs.
Highlights
Two waves of genome-wide reprogramming of DNA methylation occur during mammalian embryonic development, and have been shown to be crucial for the proper development of mammals [1,2,3,4]
When we systematically compared signal intensities of the ChIP peaks with chromatin accessibility or endogenous DNA methylation levels of the genome using non-overlapped 1 kb bins, we found that, in general, H3K4me3, H3K27ac and H3K27me3 histone modifications are clearly correlated with chromatin accessibility, with H3K4me3 having the highest correlation with chromatin accessibility than H3K27ac, and H3K27me3 being marginally correlated with chromatin accessibility
Some of the techniques, such as transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) or DNase-seq, have already been optimized to capture chromatin organization from small amount of cells or even at single-cell resolution, refining our understanding of the epigenetic regulation of cell identity to a greater extent [39,40,41,42]. Both the ATAC-seq and DNase-seq techniques rely on the abilities and processivities of Tn5 transposase or DNase enzyme, which can preferentially insert into or digest the accessible chromatin in the genome, leaving the closed chromatin regions and undetected regions indistinguishable
Summary
Two waves of genome-wide reprogramming of DNA methylation occur during mammalian embryonic development, and have been shown to be crucial for the proper development of mammals [1,2,3,4]. The dynamic transcriptome and DNA methylome of human fetal germ cells (FGCs) during development have been comprehensively analyzed by our and other groups [5,6,7]. Despite the global drastic DNA methylation erasure, FGCs maintain relatively stable transcriptome between 4 and 11 weeks after gestation. Several groups have applied the chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) strategy to mouse primordial germ cells (PGCs) at several developmental time points during sexual differentiation and meiotic initiation, and provided the genome-wide histone modification profiles of mouse PGCs [8,9,10]
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