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Cell Stem Cell. 2018 Aug 2;23(2):276-288.e8. doi: 10.1016/j.stem.2018.06.014. Epub 2018 Jul 19.

Functional Dissection of the Enhancer Repertoire in Human Embryonic Stem Cells.

Author information

1
MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, EH16 4UU, UK; Department of Clinical Genetics, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands. Electronic address: t.barakat@erasmusmc.nl.
2
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, Austria.
3
MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, EH16 4UU, UK.
4
Department of Clinical Genetics, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands.
5
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; Max Planck Institute for Informatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany.
6
MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh, EH16 4UU, UK. Electronic address: i.chambers@ed.ac.uk.

Abstract

Enhancers are genetic elements that regulate spatiotemporal gene expression. Enhancer function requires transcription factor (TF) binding and correlates with histone modifications. However, the extent to which TF binding and histone modifications functionally define active enhancers remains unclear. Here, we combine chromatin immunoprecipitation with a massively parallel reporter assay (ChIP-STARR-seq) to identify functional enhancers in human embryonic stem cells (ESCs) genome-wide in a quantitative unbiased manner. Although active enhancers associate with TFs, only a minority of regions marked by NANOG, OCT4, H3K27ac, and H3K4me1 function as enhancers, with activity markedly changing under naive versus primed culture conditions. We identify an enhancer set associated with functions extending to non-ESC-specific processes. Moreover, although transposable elements associate with putative enhancers, only some exhibit activity. Similarly, within super-enhancers, large tracts are non-functional, with activity restricted to small sub-domains. This catalog of validated enhancers provides a valuable resource for further functional dissection of the regulatory genome.

KEYWORDS:

ChIP-STARR-seq; H3K27ac; H3K4me1; NANOG; OCT4; genome-wide functional enhancer map; naive pluripotency; super-enhancers; transposable elements

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