A unique chromatin signature uncovers early developmental enhancers in humans

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature (Impact Factor: 42.35). 02/2011; 470(7333):279-83. DOI: 10.1038/nature09692
Source: PubMed

ABSTRACT Cell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of genomic sequences that control human embryonic development represents a formidable challenge. Here we show that in human embryonic stem cells (hESCs), unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, monomethylation of histone H3 at lysine 4 (H3K4me1), and low nucleosomal density. In addition, elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized hESC enhancers, and are located proximally to genes expressed in hESCs and the epiblast. In contrast, elements of the second class, which we term 'poised enhancers', are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3), and are linked to genes inactive in hESCs and instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafish embryos, poised enhancers are able to direct cell-type and stage-specific expression characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that early developmental enhancers are epigenetically pre-marked in hESCs and indicate an unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the wealth of new regulatory sequences identified here provides an invaluable resource for studies and isolation of transient, rare cell populations representing early stages of human embryogenesis.

Download full-text


Available from: Ryan Alexander Flynn, Jul 07, 2015
  • Source
    [Show abstract] [Hide abstract]
    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.
    Genome Research 03/2015; 25(4). DOI:10.1101/gr.183368.114 · 13.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Long-term exposure to peroxisome proliferator-activated receptor γ (PPARγ) agonists such as rosiglitazone induces browning of rodent and human adipocytes; however, the transcriptional mechanisms governing this phenotypic switch in adipocytes are largely unknown. Here we show that rosiglitazone-induced browning of human adipocytes activates a comprehensive gene program that leads to increased mitochondrial oxidative capacity. Once induced, this gene program and oxidative capacity are maintained independently of rosiglitazone, suggesting that additional browning factors are activated. Browning triggers reprogramming of PPARγ binding, leading to the formation of PPARγ "superenhancers" that are selective for brown-in-white (brite) adipocytes. These are highly associated with key brite-selective genes. Based on such an association, we identified an evolutionarily conserved metabolic regulator, Kruppel-like factor 11 (KLF11), as a novel browning transcription factor in human adipocytes that is required for rosiglitazone-induced browning, including the increase in mitochondrial oxidative capacity. KLF11 is directly induced by PPARγ and appears to cooperate with PPARγ in a feed-forward manner to activate and maintain the brite-selective gene program. © 2015 Loft et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 12/2014; 29(1). DOI:10.1101/gad.250829.114 · 12.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Epigenetic landscapes represent how cells regulate gene activity. To understand their effect on gene regulation, it is important to detect their occupancy in the genome. Unlike transcription factors whose binding regions are limited to narrow regions, histone modification marks are enriched over broader areas. The stochastic characteristics unique to each mark make it hard to detect their enrichment. Classically, a predefined window has been used to detect their enrichment. However, these approaches heavily rely on the predetermined parameters. Also, the window-based approaches cannot handle the enrichment of multiple marks. We propose a novel algorithm, called SeqW, to detect enrichment of multiple histone modification marks. SeqW applies a zooming approach to detect a broadly enriched domain. The zooming approach helps domain detection by increasing signal-to-noise ratio. The borders of the domains are detected by studying the characteristics of signals in the wavelet domain. We show that SeqW outperformed previous predictors in detecting broad peaks. Also, we applied SeqW in studying spatial combinations of histone modification patterns.
    Journal of Computational Biology 11/2014; 21(11). DOI:10.1089/cmb.2014.0095 · 1.67 Impact Factor