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A unique chromatin signature uncovers early developmental enhancers in humans
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Alvaro Rada-Iglesias,1 RuchiBajpai,1 TomekSwigut,1 Samantha A. Brugmann,1 Ryan A. Flynn1 & Joanna Wysocka
Nature Volume: 470, Pages: 279¨C283 Date published: (10 February 2011) DOI: doi:10.1038/nature09692 Received 04 August 2010 Accepted 25 November 2010 Published online 15 December 2010
ÕªÒª£ºCell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with thecellular environment1, 2. However, identification of genomic sequences that control human embryonic development represents a formidable challenge3. 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, monomethylationof histoneH3 at lysine 4 (H3K4me1), and low nucleosomaldensity. In addition, elements of the first class are distinguished by the acetylationof histoneH3 at lysine 27 (H3K27ac), overlap with previously characterized hESCenhancers, and are located proximally to genes expressed in hESCsand the epiblast. In contrast, elements of the second class, which we term ¡®poised enhancers¡¯, are distinguished by the absence of H3K27ac, enrichment of histoneH3 lysine 27 trimethylation(H3K27me3), and are linked to genes inactive in hESCsand instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCsto neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafishembryos, 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 hESCsand 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.
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