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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    • "Mean Wiggler values were calculated in 10-bp bins (Gerstein et al. 2012). To normalize variations between biological replicates , we modified a previously described method to perform Z-score transformation by subtracting the mean Wiggler value across the genome and dividing by the standard deviation of the genome-wide Wiggler subtraction value (Xie et al. 2013). "
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    ABSTRACT: The holistic role of DNA methylation in the organization of the cancer epigenome is not well understood. Here we perform a comprehensive, high-resolution analysis of chromatin structure to compare the landscapes of HCT116 colon cancer cells and a DNA methylation-deficient derivative. The NOMe-seq accessibility assay unexpectedly revealed symmetrical and transcription-independent nucleosomal phasing across active, poised, and inactive genomic elements. DNA methylation abolished this phasing primarily at enhancers and CpG island (CGI) promoters, with little effect on insulators and non-CGI promoters. Abolishment of DNA methylation led to the context-specific reestablishment of the poised and active states of normal colon cells, which were marked in methylation-deficient cells by distinct H3K27 modifications and the presence of either well-phased nucleosomes or nucleosome-depleted regions, respectively. At higher-order genomic scales, we found that long, H3K9me3-marked domains had lower accessibility, consistent with a more compact chromatin structure. Taken together, our results demonstrate the nuanced and context-dependent role of DNA methylation in the functional, multiscale organization of cancer epigenomes. © 2015 Lay et al.; Published by Cold Spring Harbor Laboratory Press.
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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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    • "In contrast, stem cell-specific CG-poor promoters active in ESCs are mostly repressed solely by DNA methylation in later stages of development (Xie et al. 2013; Gifford et al. 2013). "
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    ABSTRACT: Lineage-specific phenotypes are the result of characteristic cellular gene expression patterns. Several epigenetic mechanisms have evolved that control the generation of these different phenotypes from the same genotype. Stem cells, in order to prevent differentiation, need to repress lineage-specific transcription factors and maintain the activity of stemness genes that promote self-renewal and pluripotency. In this context differentiation is basically a process governed by changes in gene activity during development that alter the stemness-specific epigenome towards lineage-specific patterns, often in response to transient factors or environmental stimuli. Sophisticated networks of protein complexes maintain epigenomic states in stem cells and determined cells after lineage decision and ensure their transmission through cell division. In addition, they are also essential for the epigenetic changes happening during differentiation induction that are crucial for lineage specification. The Polycomb group of genes codes for a variety of proteins that maintain repressive chromatin states. They are part of a complex cellular memory system that creates a layer of epigenetic information on top of the DNA sequence that ensures the maintenance and transmission of cell-specific expression patterns.
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