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

Author

Listed:
  • Xinchen Wang

    (Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology
    Columbia University)

  • Liang He

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology)

  • 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
    Beth Israel Deaconess Medical Center
    University of Hohenheim
    Harvard University)

  • Manolis Kellis

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology)

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.

Suggested Citation

  • Xinchen Wang & Liang He & Sarah M. Goggin & Alham Saadat & Li Wang & Nasa Sinnott-Armstrong & Melina Claussnitzer & Manolis Kellis, 2018. "High-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07746-1
    DOI: 10.1038/s41467-018-07746-1
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    Cited by:

    1. Carlos Company & Matthias Jürgen Schmitt & Yuliia Dramaretska & Michela Serresi & Sonia Kertalli & Ben Jiang & Jiang-An Yin & Adriano Aguzzi & Iros Barozzi & Gaetano Gargiulo, 2024. "Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Anat Kreimer & Tal Ashuach & Fumitaka Inoue & Alex Khodaverdian & Chengyu Deng & Nir Yosef & Nadav Ahituv, 2022. "Massively parallel reporter perturbation assays uncover temporal regulatory architecture during neural differentiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. David Santiago-Algarra & Charbel Souaid & Himanshu Singh & Lan T. M. Dao & Saadat Hussain & Alejandra Medina-Rivera & Lucia Ramirez-Navarro & Jaime A. Castro-Mondragon & Nori Sadouni & Guillaume Charb, 2021. "Epromoters function as a hub to recruit key transcription factors required for the inflammatory response," Nature Communications, Nature, vol. 12(1), pages 1-18, December.

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