A unique chromatin signature uncovers early developmental enhancers in humans

By Á. Rada-Iglesias, R. Bajpai, T. Swigut, S. Brugmann, Ryan A. Flynn, J. Wysocka. Nature, 2010

2,234 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/982c7e0949733af4774449dd9c4c93f190f1c5d6

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Citations in the corpus

Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells (2014, positive): “(H3K27ac), which marks promoters and enhancers that are ‘active’ in a given cell state (Bulger and Groudine, 2011; Creyghton et al., 2010; Ernst et al., 2011; Hon et al., 2009; Rada-Iglesias et al., 2011; Visel et al., 2009).”
Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin (2020, background): “For example, deposition of the histone modification H3K4me1 has been shown to prime regulatory elements, biasing cells for differentiation (Lara-Astiaso et al., 2014; Rada-Iglesias et al., 2011) or immune cell activation (Heinz et al.”
Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers (2014, positive): “Previous work suggests that enhancer chromatin undergoes a progression from a closed state to an open state required for transcription factor binding 14, 41–43 .”
Enhancer function: new insights into the regulation of tissue-specific gene expression (2011, positive): “These results indicate that active and poised enhancers can by distinguished by the presence of H3K27ac or H3K27me3, respectivel”
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes (2013, positive): “…factors to recruit RNA Pol II to the promoters of target genes (Borggrefe and Yue, 2011; Conaway and Conaway, 2011; Kornberg, 2005; Malik and Roeder, 2010) and is essential for maintenance of ESC state and embryonic development (Ito et al., 2000; Kagey et al., 2010; Risley et al., 2010).”
c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells (2012, positive): “The p300 binding sites are sorted into 100 bins based on the H3k27ac level, an estimate of enhancer activity (Creyghton et al., 2010; Rada-Iglesias et al., 2011)).”
Super-enhancers in the control of cell identity and disease. (2013, neutral): “The set of enhancers that control any one cell’s gene expression program is probably best defined in murine embryonic stem cells (ESCs).”
H3K4me3 breadth is linked to cell identity and transcriptional consistency (2014, background): “For example, subtypes of enhancers direct the high expression of cell identity genes (Parker et al., 2013; Rada-Iglesias et al., 2011; Whyte et al., 2013).”
Latent enhancers activated by stimulation in differentiated cells. (2013, neutral): “Levels of H3K27me3, H3K27me2, and H3K9me3 were undetectable or very low at all latent enhancers tested (Figures 6A and S6A), indicating that these marks were not involved in maintenance of basal repression.”
Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage (2012, positive): “…modification patterns can distinguish active enhancers (which correlate with tissue-specific expression) from poised enhancers (which correlate with potential gene expres- sion later in development) (Creyghton et al., 2010; Ernst et al., 2011; Rada-Iglesias et al., 2011; Zentner et al., 2011).”
Activity-by-Contact model of enhancer-promoter regulation from thousands of CRISPR perturbations (2019, background): “DNase accessibility and acetylation of H3K27 are commonly used to identify enhancer elements 44,45 , and are predictive of the expression of nearby genes and enhancer activity in plasmid based reporter assays 46–48 We note that this calculation of enhancer activity is the same for a given element…”