High-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human

Xinchen Wang, Liang He, Sarah M. Goggin, Alham Saadat, Li Wang, Nasa Sinnott-Armstrong, Melina Claussnitzer () and Manolis Kellis ()
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Xinchen Wang: Massachusetts Institute of Technology
Liang He: Broad Institute of MIT and Harvard
Sarah M. Goggin: Broad Institute of MIT and Harvard
Alham Saadat: Broad Institute of MIT and Harvard
Li Wang: Broad Institute of MIT and Harvard
Nasa Sinnott-Armstrong: Broad Institute of MIT and Harvard
Melina Claussnitzer: Broad Institute of MIT and Harvard
Manolis Kellis: Broad Institute of MIT and Harvard

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Genome-wide epigenomic maps have revealed millions of putative enhancers and promoters, but experimental validation of their function and high-resolution dissection of their driver nucleotides remain limited. Here, we present HiDRA (High-resolution Dissection of Regulatory Activity), a combined experimental and computational method for high-resolution genome-wide testing and dissection of putative regulatory regions. We test ~7 million accessible DNA fragments in a single experiment, by coupling accessible chromatin extraction with self-transcribing episomal reporters (ATAC-STARR-seq). By design, fragments are highly overlapping in densely-sampled accessible regions, enabling us to pinpoint driver regulatory nucleotides by exploiting differences in activity between partially-overlapping fragments using a machine learning model (SHARPR-RE). In GM12878 lymphoblastoid cells, we find ~65,000 regions showing enhancer function, and pinpoint ~13,000 high-resolution driver elements. These are enriched for regulatory motifs, evolutionarily-conserved nucleotides, and disease-associated genetic variants from genome-wide association studies. Overall, HiDRA provides a high-throughput, high-resolution approach for dissecting regulatory regions and driver nucleotides.

Date: 2018
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DOI: 10.1038/s41467-018-07746-1

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