Global reference mapping of human transcription factor footprints

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, Audra Johnson, Mark Frerker, Michael Buckley, Rajinder Kaul, Wouter Meuleman and John A. Stamatoyannopoulos ()
Additional contact information
Jeff Vierstra: Altius Institute for Biomedical Sciences
John Lazar: Altius Institute for Biomedical Sciences
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

Nature, 2020, vol. 583, issue 7818, 729-736

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2528-x

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