High-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human [31.12.18]
In this Nature Communication, Prof. Claussnitzer (Chair Dept. Nutritional Science at the University of Hohenheim) and colleages from the US present 'High-resolution Dissection of Regulatory Activity' (HiDRA), a high-throughput experimental assay for testing transcriptional regulatory activity across millions of DNA fragments, and for inferring high-resolution driver elements within them. (Wang et al, 2018) HiDRA merges three experimental and computational approaches to study how disease-related variants in the noncoding genome impact gene expression.
Source: Wang, Xinchen; He, Liang; Goggin, Sarah M.; Saadat, Alham; Wang, Li; Sinnott-Armstrong, Nasa et al. (2018): High-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human. In: Nature communications 9 (1), S. 5380. DOI: 10.1038/s41467-018-07746-1.
Original Article
Wang X1,2,3,4, He L2,3, Goggin SM2, Saadat A2, Wang L2, Sinnott-Armstrong N2, Claussnitzer M5,6,7,8, Kellis M9,10. (2018): High-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human. In: Nature communications 9 (1), S. 5380. DOI: 10.1038/s41467-018-07746-1.
Author information
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
- Institute for Genomic Medicine, Columbia University, New York, NY, 10024, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. melina@broadinstitute.org.
- Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. melina@broadinstitute.org.
- Institute of Nutritional Science, University of Hohenheim, Garbenstrasse 30, 70599, Stuttgart, Germany. melina@broadinstitute.org.
- Harvard Medical School, Harvard University, Boston, MA, 02215, USA. melina@broadinstitute.org.
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. manoli@mit.edu.
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. manoli@mit.edu.
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.
