Functional Dissection of the Enhancer Repertoire in Human Embryonic Stem Cells
Cell Stem Cell. 2018-08-02;23(2):276-288.e8.
- 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.
- Consortium data used in this publication
- High-throughput sequencing data generated in this study have been submitted to the Gene Expression Omnibus (GEO): accession code GEO: GSE99631, to the Sequence Read Archive (SRA): accession codes SRA: SRP108517, SRA: SRP108518, SRA: SRP108519, and SRA: SRP108520. A BioProject for this study has also been registered: PRJNA389108. GSE99627--The functional enhancer repertoire of human embryonic stem cells [ChIP-seq]; GSE99628--The functional enhancer repertoire of human embryonic stem cells [isolated plasmid DNA-seq]; GSE99629--The functional enhancer repertoire of human embryonic stem cells [plasmid DNA-seq]; GSE99630--The functional enhancer repertoire of human embryonic stem cells [STARR-RNA-seq]