Rxivist logo

Global reference mapping and dynamics of human transcription factor footprints

By 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, John A Stamatoyannopoulos

Posted 01 Feb 2020
bioRxiv DOI: 10.1101/2020.01.31.927798 (published DOI: 10.1038/s41586-020-2528-x)

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 traits, yet it remains challenging to distinguish variants that impact regulatory function. Genomic DNase I footprinting enables quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin. However, to date only a small fraction of such sites have been precisely resolved on the human genome sequence. 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 at nucleotide resolution ~4.5 million compact genomic elements encoding transcription factor occupancy. We map the fine-scale structure of ~1.6 million DHS and show that the overwhelming majority is populated by well-spaced sites of single transcription factor:DNA interaction. Cell context-dependent cis-regulation is chiefly executed by wholesale actuation of accessibility at regulatory DNA versus by differential transcription factor occupancy within accessible elements. We show further that the well-described enrichment of disease- and phenotypic trait-associated genetic variants in regulatory regions is almost entirely attributable variants localizing within footprints, and that functional variants impacting transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find that the global density of human genetic variation is markedly increased within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a new framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation.

Download data

  • Downloaded 1,498 times
  • Download rankings, all-time:
    • Site-wide: 6,727 out of 100,745
    • In genomics: 1,032 out of 6,246
  • Year to date:
    • Site-wide: 1,332 out of 100,745
  • Since beginning of last month:
    • Site-wide: 17,567 out of 100,745

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide


Sign up for the Rxivist weekly newsletter! (Click here for more details.)


  • 20 Oct 2020: Support for sorting preprints using Twitter activity has been removed, at least temporarily, until a new source of social media activity data becomes available.
  • 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
  • 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
  • 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
  • 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
  • 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
  • 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
  • 22 Jan 2019: Nature just published an article about Rxivist and our data.
  • 13 Jan 2019: The Rxivist preprint is live!