Epigenomic Analysis of Multilineage Differentiation of Human Embryonic Stem Cells

Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
Cell (Impact Factor: 32.24). 05/2013; 153(5). DOI: 10.1016/j.cell.2013.04.022
Source: PubMed


Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in nonexpressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation.

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    • "This increased repetitive element expression may result from aberrant epigenetic repression and could contribute to increased genome instability (Figure 1E). Anomalous repetitive element expression has been associated with embryonic stem cells (ESCs) (Xie et al., 2013) but not aging. Examination of the genes near the dysregulated LTR elements, LINEs, and SINEs revealed 194, 127, and 72 genes, respectively. "

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    • "H3K27me3 gives stronger enrichment signal with the exons definition for all cell lines except H1-hESC, which performs best with the ≤5 kb locus definition (Supplementary Fig. S6). This may be indicative of a different regulatory regime for H3K27me3 in embryonic stem cells versus the other cell lines, consistent with current literature (Xie et al., 2013). H3K4me1 is considered a distal activating mark (Dong et al., 2012), and exhibits stronger enrichment signal with the nearest TSS locus definition in GM12878 and HepG2 but stronger signal with ≤5 kb in H1-hESC, HeLa-S3 and K562 (Supplementary Fig. S7). "
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