Genomweite, hochauflösende Analyse von transkriptionell aktiven, regulatorischen Regionen und deren funktionellen Sequenzen  [31.12.18]

In einer aktuellen Publikation in 'Nature Communications' präsentieren Prof. Claussnitzer (Lehrstuhlinhaberin "Ernährungswissenschaften" an der Universität Hohenheim in Stuttgart) und ihre Kollegen aus den USA 'High-resolution Dissection of Regulatory Activity' (HiDRA), einen Hochdurchsatz-Assay zum Nachweis transkriptioneller Aktivität sowie zur hochauflösenden Identifikation regulatorischer "Driver"-Sequenzen im menschlichen Genom (Wang et al, 2018). HiDRA kombiniert dabei drei experimentelle bzw. rechnergestützte Methoden, um zu untersuchen, wie krankheitsrelevante Variationen in nicht kodierenden Genom-Bereichen die Genexpression beeinflussen.

Quelle: 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.

Originalpublikation

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

  1. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  2. Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
  3. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  4. Institute for Genomic Medicine, Columbia University, New York, NY, 10024, USA.
  5. Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. melina@broadinstitute.org.
  6. Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. melina@broadinstitute.org.
  7. Institute of Nutritional Science, University of Hohenheim, Garbenstrasse 30, 70599, Stuttgart, Germany. melina@broadinstitute.org.
  8. Harvard Medical School, Harvard University, Boston, MA, 02215, USA. melina@broadinstitute.org.
  9. Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. manoli@mit.edu.
  10. 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.

Zur Pressemitteilung des Broad Instituts: www.broadinstitute.org/news/new-multi-pronged-method-probes-how-noncoding-dna-affects-gene-expression


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Quelle: 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.