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Dynamics of enhancer chromatin signatures mark the transition from pluripotency to cell specification during embryogenesis

ABSTRACT: The generation of distinctive cell types that form different tissues and organs requires precise, temporal and spatial control of gene expression. This depends on specific cis-regulatory elements distributed in the non-coding DNA surrounding their target genes. Studies performed on mammalian embryonic stem cells and Drosophila embryos suggest that active enhancers form part of a defined chromatin landscape marked by histone H3 lysine 4 mono-methylation (H3K4me1) and histone H3 lysine 27 acetylation (H3K27ac). Nevertheless, little is known about the dynamics and the potential roles of these marks during vertebrate embryogenesis. Here we provide genomic maps of H3K4me1/me3 and H3K27ac at four developmental time-points of zebrafish embryogenesis and analyze embryonic enhancer activity. We find that: (i) changes in H3K27ac enrichment at enhancers accompany the shift from pluripotency to tissue-specific gene expression; (ii) in early embryos, the peaks of H3K27ac enrichment are bound by pluripotent factors such as Nanog; (iii) the degree of evolutionary conservation is higher for enhancers that become marked by H3K27ac at the end of gastrulation suggesting their implication in the establishment of the most conserved (phylotypic) transcriptome that is known to occur later at the pharyngula stage.

ORGANISM(S): Danio rerio

PROVIDER: GSE32483 | GEO | 2012/05/08

SECONDARY ACCESSION(S): PRJNA147789

REPOSITORIES: GEO

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Project description:Cell fate transitions involve integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of the genomic sequences that control the earliest steps of 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, and monomethylation of histone H3 at lysine 4 (H3K4me1). In addition, the elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized enhancers active in hESCs, and are generally located proximally to genes expressed in hESCs and in the epiblast. In contrast, the elements within the second class, which we termed M-bM-^@M-^\poised enhancersM-bM-^@M-^], are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3) and are linked to genes inactive in hESCs and involved in orchestrating early steps in mammalian development, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of these elements acquires a chromatin signature associated with active enhancers. Remarkably, when assayed in zebrafish embryos, human poised enhancer elements are able to direct cell type and stage specific expression patterns characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that enhancers are epigenetically pre-marked and suggest a heretofore unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the unique chromatin signature associated with poised enhancers allowed us to uncover over 2,000 putative developmental regulatory sequences, thereby creating an invaluable resource for future studies and isolation of transient, rare cell populations representing early steps of human development. For GSM602289-90: RNA-seq experiments in human ESC and neuroectodermal (NEC) speheres For GSM602291-303: Genome-wide analysis of p300, H3K4me3, H3K4me1, H3K27me3 and H3K27ac in human embryonic stem cells (ESC) and neuroectoderm cells (NEC). Additionally, in H9 ESC ChIP-seq were alsoe obtained for BRG1 and FAIRE-seq was also performed.

Project description:Cell fate transitions involve integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of the genomic sequences that control the earliest steps of 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, and monomethylation of histone H3 at lysine 4 (H3K4me1). In addition, the elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized enhancers active in hESCs, and are generally located proximally to genes expressed in hESCs and in the epiblast. In contrast, the elements within the second class, which we termed “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 involved in orchestrating early steps in mammalian development, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of these elements acquires a chromatin signature associated with active enhancers. Remarkably, when assayed in zebrafish embryos, human poised enhancer elements are able to direct cell type and stage specific expression patterns characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that enhancers are epigenetically pre-marked and suggest a heretofore unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the unique chromatin signature associated with poised enhancers allowed us to uncover over 2,000 putative developmental regulatory sequences, thereby creating an invaluable resource for future studies and isolation of transient, rare cell populations representing early steps of human development.

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Dynamics of enhancer chromatin signatures mark the transition from pluripotency to cell specification during embryogenesis

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