Epigenomic Analysis of Multi-lineage Differentiation of Human Embryonic Stem Cells

By Wei Xie, Matthew D. Schultz, Ryan Lister, Zhonggang Hou, N. Rajagopal, P. Ray, J. Whitaker, Shulan Tian, R. D. Hawkins, Danny Leung and 34 more. Cell, 2013

709 citations recorded by the source corpus.

SUMMARY 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 non-expressing 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c54f2746eb9be27dcda1b2475e11a6d5fe70fc28

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Citations in the corpus

H3K4me3 breadth is linked to cell identity and transcriptional consistency (2014, background): “…super-enhancers (regions intensely bound by mediator and cell-speciﬁc transcription factors) (Whyte et al., 2013), stretch enhancers (extended enhancer regions) (Parker et al., 2013), and DNA methylation canyons or valleys (large hypomethylated regions) (Jeong et al., 2014; Xie et al., 2013).”
Developmental regulation of human cortex transcription and its clinical relevance at base resolution (2014, positive): “We also explored the cell-type specificity of these DERs, and respective intronic and intergenic expression, using publicly available RNA-seq data from human stem cells 16 and somatic adult tissues 17 .”
Gene Body Methylation can alter Gene Expression and is a Therapeutic Target in Cancer (2014, methodology): “We normalized experimental data into wiggler values (Bernstein et al., 2012), which were further transformed into z scores to normalize variations between experiments based on a previously described method (Xie et al., 2013).”
A Reference Methylome Database and Analysis Pipeline to Facilitate Integrative and Comparative Epigenomics (2013, background): “recently reported a distinct class of genomic regions, called DNA methylation valleys, which contain early developmental regulatory genes [35].”
HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient (2017, positive): “Importantly, the same relationships were also supported by previous analysis of gene expression data (additional file 1: Figure S2) in the same cell types [28].”
Integrative analysis of 111 reference human epigenomes (2015, background): “Extended data (1-12), supplementary figures (S1-S13), supplementary tables (S1-S6) are available in the online version of the paper.”
Epigenomic Signatures of Neuronal Diversity in the Mammalian Brain (2015, background): “DMVs are highly overlapping across adult cell types and fetal cortex (Figure S7A), in line with previous evidence (Xie et al., 2013) suggesting they may be established early during development and subsequently maintained.”
Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal (2014, background): “Anomalous repetitive element expression has been associated with embryonic stem cells (ESCs) (Xie et al., 2013) but not aging.”
DNA methylation: a historical perspective. (2022, neutral): “The strong signal at the bottom of the lanes stems from the sensitive detection of canonically unmethylated CGIs.”
A Comparative Encyclopedia of DNA Elements in the Mouse Genome (2014, background): “Of the 164,428 chromatin based enhancer predictions that have human orthologs, 40% (64,962) of them are predicted as an enhancer in human (Supplementary Table 32).”