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Global reference mapping of human transcription factor footprints

Author

Listed:
  • Jeff Vierstra

    (Altius Institute for Biomedical Sciences)

  • John Lazar

    (Altius Institute for Biomedical Sciences
    University of Washington)

  • Richard Sandstrom

    (Altius Institute for Biomedical Sciences)

  • Jessica Halow

    (Altius Institute for Biomedical Sciences)

  • Kristen Lee

    (Altius Institute for Biomedical Sciences)

  • Daniel Bates

    (Altius Institute for Biomedical Sciences)

  • Morgan Diegel

    (Altius Institute for Biomedical Sciences)

  • Douglas Dunn

    (Altius Institute for Biomedical Sciences)

  • Fidencio Neri

    (Altius Institute for Biomedical Sciences)

  • Eric Haugen

    (Altius Institute for Biomedical Sciences)

  • Eric Rynes

    (Altius Institute for Biomedical Sciences)

  • Alex Reynolds

    (Altius Institute for Biomedical Sciences)

  • Jemma Nelson

    (Altius Institute for Biomedical Sciences)

  • Audra Johnson

    (Altius Institute for Biomedical Sciences)

  • Mark Frerker

    (Altius Institute for Biomedical Sciences)

  • Michael Buckley

    (Altius Institute for Biomedical Sciences)

  • Rajinder Kaul

    (Altius Institute for Biomedical Sciences)

  • Wouter Meuleman

    (Altius Institute for Biomedical Sciences)

  • John A. Stamatoyannopoulos

    (Altius Institute for Biomedical Sciences
    University of Washington
    University of Washington)

Abstract

Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, but it remains challenging to distinguish variants that affect regulatory function2. Genomic DNase I footprinting enables the quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin3–6. However, only a small fraction of such sites have been precisely resolved on the human genome sequence6. Here, to enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate about 4.5 million compact genomic elements that encode transcription factor occupancy at nucleotide resolution. We map the fine-scale structure within about 1.6 million DNase I-hypersensitive sites and show that the overwhelming majority are populated by well-spaced sites of single transcription factor–DNA interaction. Cell-context-dependent cis-regulation is chiefly executed by wholesale modulation of accessibility at regulatory DNA rather than by differential transcription factor occupancy within accessible elements. We also show that the enrichment of genetic variants associated with diseases or phenotypic traits in regulatory regions1,7 is almost entirely attributable to variants within footprints, and that functional variants that affect transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find increased density of human genetic variation within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation.

Suggested Citation

  • Jeff Vierstra & John Lazar & Richard Sandstrom & Jessica Halow & Kristen Lee & Daniel Bates & Morgan Diegel & Douglas Dunn & Fidencio Neri & Eric Haugen & Eric Rynes & Alex Reynolds & Jemma Nelson & A, 2020. "Global reference mapping of human transcription factor footprints," Nature, Nature, vol. 583(7818), pages 729-736, July.
  • Handle: RePEc:nat:nature:v:583:y:2020:i:7818:d:10.1038_s41586-020-2528-x
    DOI: 10.1038/s41586-020-2528-x
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    Citations

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    Cited by:

    1. Shengen Shawn Hu & Lin Liu & Qi Li & Wenjing Ma & Michael J. Guertin & Clifford A. Meyer & Ke Deng & Tingting Zhang & Chongzhi Zang, 2022. "Intrinsic bias estimation for improved analysis of bulk and single-cell chromatin accessibility profiles using SELMA," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Junhao Li & Manoj K. Jaiswal & Jo-Fan Chien & Alexey Kozlenkov & Jinyoung Jung & Ping Zhou & Mahammad Gardashli & Luc J. Pregent & Erica Engelberg-Cook & Dennis W. Dickson & Veronique V. Belzil & Eran, 2023. "Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Alexendar R. Perez & Laura Sala & Richard K. Perez & Joana A. Vidigal, 2021. "CSC software corrects off-target mediated gRNA depletion in CRISPR-Cas9 essentiality screens," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. Kathleen Shah & Muralidhara Rao Maradana & M. Joaquina Delàs & Amina Metidji & Frederike Graelmann & Miriam Llorian & Probir Chakravarty & Ying Li & Mauro Tolaini & Michael Shapiro & Gavin Kelly & Chr, 2022. "Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Hillary Koch & Cheryl A. Keller & Guanjue Xiang & Belinda Giardine & Feipeng Zhang & Yicheng Wang & Ross C. Hardison & Qunhua Li, 2022. "CLIMB: High-dimensional association detection in large scale genomic data," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Konsta Karttunen & Divyesh Patel & Jihan Xia & Liangru Fei & Kimmo Palin & Lauri Aaltonen & Biswajyoti Sahu, 2023. "Transposable elements as tissue-specific enhancers in cancers of endodermal lineage," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    7. Kerryn Elliott & Vinod Kumar Singh & Martin Boström & Erik Larsson, 2023. "Base-resolution UV footprinting by sequencing reveals distinctive damage signatures for DNA-binding proteins," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    8. Alan Y. Du & Jason D. Chobirko & Xiaoyu Zhuo & Cédric Feschotte & Ting Wang, 2024. "Regulatory transposable elements in the encyclopedia of DNA elements," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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