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Short tandem repeats bind transcription factors to tune eukaryotic gene expression | bioRxiv
<!DOCTYPE html> <html lang="en" dir="ltr" xmlns="http://www.w3.org/1999/xhtml" xmlns:mml="http://www.w3.org/1998/Math/MathML"> <head prefix="og: http://ogp.me/ns# article: http://ogp.me/ns/article# book: http://ogp.me/ns/book#" > <!--[if IE]><![endif]--> <link rel="dns-prefetch" href="//d33xdlntwy0kbs.cloudfront.net" /> <link rel="dns-prefetch" href="//www.google.com" /> <link rel="dns-prefetch" href="//scholar.google.com" /> <link rel="dns-prefetch" href="//www.googletagmanager.com" /> <meta http-equiv="Content-Type" content="text/html; charset=utf-8" /> <link rel="shortcut icon" href="https://www.biorxiv.org/sites/default/files/images/favicon.ico" type="image/vnd.microsoft.icon" /> <meta name="viewport" content="width=device-width, initial-scale=1" /> <link rel="alternate" type="application/pdf" title="Full Text (PDF)" href="/content/10.1101/2022.05.24.493321v2.full.pdf" /> <link rel="alternate" type="text/plain" title="Full Text (Plain)" href="/content/10.1101/2022.05.24.493321v2.full.txt" /> <meta name="type" content="article" /> <meta name="category" content="article" /> <meta name="HW.identifier" content="/biorxiv/early/2022/05/30/2022.05.24.493321.atom" /> <meta name="HW.pisa" content="biorxiv;2022.05.24.493321v2" /> <meta name="DC.Format" content="text/html" /> <meta name="DC.Language" content="en" /> <meta name="DC.Title" content="Short tandem repeats bind transcription factors to tune eukaryotic gene expression" /> <meta name="DC.Identifier" content="10.1101/2022.05.24.493321" /> <meta name="DC.Date" content="2022-05-30" /> <meta name="DC.Publisher" content="Cold Spring Harbor Laboratory" /> <meta name="DC.Rights" content="© 2022, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-NonCommercial-NoDerivs 4.0 International), CC BY-NC-ND 4.0, as described at http://creativecommons.org/licenses/by-nc-nd/4.0/" /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Description" content="Short tandem repeats (STRs) are enriched in eukaryotic cis -regulatory elements and their polymorphisms alter gene expression, yet how they regulate transcription remains unknown. We find that STRs can modulate transcription factor (TF)-DNA affinities and on rates by up to 70-fold by directly binding TF DNA-binding domains, with energetic impacts approaching or exceeding mutations to consensus sites. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density near motifs to speed target search. Confirming that STRs also impact TF binding in cells, neural networks trained only on in vivo occupancies predict identical effects to those observed in vitro . Approximately 90% of TFs preferentially bind STRs that need not resemble known motifs, providing a novel cis -regulatory mechanism to target TFs to cognate sites. ### Competing Interest Statement The authors have declared no competing interest." /> <meta name="DC.Contributor" content="Connor A. Horton" /> <meta name="DC.Contributor" content="Amr M. Alexandari" /> <meta name="DC.Contributor" content="Michael G. B. Hayes" /> <meta name="DC.Contributor" content="Emil Marklund" /> <meta name="DC.Contributor" content="Julia M. Schaepe" /> <meta name="DC.Contributor" content="Arjun K. Aditham" /> <meta name="DC.Contributor" content="Nilay Shah" /> <meta name="DC.Contributor" content="Avanti Shrikumar" /> <meta name="DC.Contributor" content="Ariel Afek" /> <meta name="DC.Contributor" content="William J. Greenleaf" /> <meta name="DC.Contributor" content="Raluca Gordân" /> <meta name="DC.Contributor" content="Julia Zeitlinger" /> <meta name="DC.Contributor" content="Anshul Kundaje" /> <meta name="DC.Contributor" content="Polly M. Fordyce" /> <meta name="article:published_time" content="2022-05-30" /> <meta name="article:section" content="New Results" /> <meta name="citation_title" content="Short tandem repeats bind transcription factors to tune eukaryotic gene expression" /> <meta name="citation_abstract" lang="en" content="<h3>Abstract</h3> <p>Short tandem repeats (STRs) are enriched in eukaryotic <i>cis</i>-regulatory elements and their polymorphisms alter gene expression, yet how they regulate transcription remains unknown. We find that STRs can modulate transcription factor (TF)-DNA affinities and on rates by up to 70-fold by directly binding TF DNA-binding domains, with energetic impacts approaching or exceeding mutations to consensus sites. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density near motifs to speed target search. Confirming that STRs also impact TF binding in cells, neural networks trained only on <i>in vivo</i> occupancies predict identical effects to those observed <i>in vitro</i>. Approximately 90% of TFs preferentially bind STRs that need not resemble known motifs, providing a novel <i>cis</i>-regulatory mechanism to target TFs to cognate sites.</p>" /> <meta name="citation_journal_title" content="bioRxiv" /> <meta name="citation_publisher" content="Cold Spring Harbor Laboratory" /> <meta name="citation_publication_date" content="2022/01/01" /> <meta name="citation_mjid" content="biorxiv;2022.05.24.493321v2" /> <meta name="citation_id" content="2022.05.24.493321v2" /> <meta name="citation_public_url" content="https://www.biorxiv.org/content/10.1101/2022.05.24.493321v2" /> <meta name="citation_abstract_html_url" content="https://www.biorxiv.org/content/10.1101/2022.05.24.493321v2.abstract" /> <meta name="citation_full_html_url" content="https://www.biorxiv.org/content/10.1101/2022.05.24.493321v2.full" /> <meta name="citation_pdf_url" content="https://www.biorxiv.org/content/biorxiv/early/2022/05/30/2022.05.24.493321.full.pdf" /> <meta name="citation_doi" content="10.1101/2022.05.24.493321" /> <meta name="citation_num_pages" content="22" /> <meta name="citation_article_type" content="Article" /> <meta name="citation_section" content="New Results" /> <meta name="citation_firstpage" content="2022.05.24.493321" /> <meta name="citation_author" content="Connor A. Horton" /> <meta name="citation_author_institution" content="Department of Genetics, Stanford University" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0001-6018-3556" /> <meta name="citation_author" content="Amr M. Alexandari" /> <meta name="citation_author_institution" content="Department of Computer Science, Stanford University" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0001-8655-8109" /> <meta name="citation_author" content="Michael G. B. Hayes" /> <meta name="citation_author_institution" content="Department of Genetics, Stanford University" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0001-5315-7042" /> <meta name="citation_author" content="Emil Marklund" /> <meta name="citation_author_institution" content="Department of Genetics, Stanford University" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0002-1150-7304" /> <meta name="citation_author" content="Julia M. Schaepe" /> <meta name="citation_author_institution" content="Department of Bioengineering, Stanford University" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0003-0416-0469" /> <meta name="citation_author" content="Arjun K. Aditham" /> <meta name="citation_author_institution" content="Department of Bioengineering, Stanford University" /> <meta name="citation_author_institution" content="ChEM-H Institute, Stanford University" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0002-9839-7733" /> <meta name="citation_author" content="Nilay Shah" /> <meta name="citation_author_institution" content="Stowers Institute for Medical Research" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0002-0081-8537" /> <meta name="citation_author" content="Avanti Shrikumar" /> <meta name="citation_author_institution" content="Department of Computer Science, Stanford University" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0002-6443-4671" /> <meta name="citation_author" content="Ariel Afek" /> <meta name="citation_author_institution" content="Center for Genomic and Computational Biology, Duke University School of Medicine" /> <meta name="citation_author_institution" content="Department of Biostatistics and Bioinformatics, Duke University School of Medicine" /> <meta name="citation_author_orcid" content="http://orcid.org/0000-0001-8584-9879" /> <meta name="citation_author" content="William J. 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S. A. 113, 12226–12231 (2016)." /> <meta name="twitter:title" content="Short tandem repeats bind transcription factors to tune eukaryotic gene expression" /> <meta name="twitter:site" content="@biorxivpreprint" /> <meta name="twitter:card" content="summary" /> <meta name="twitter:image" content="https://www.biorxiv.org/sites/default/files/images/biorxiv_logo_homepage7-5-small.png" /> <meta name="twitter:description" content="Short tandem repeats (STRs) are enriched in eukaryotic cis -regulatory elements and their polymorphisms alter gene expression, yet how they regulate transcription remains unknown. We find that STRs can modulate transcription factor (TF)-DNA affinities and on rates by up to 70-fold by directly binding TF DNA-binding domains, with energetic impacts approaching or exceeding mutations to consensus sites. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density near motifs to speed target search. Confirming that STRs also impact TF binding in cells, neural networks trained only on in vivo occupancies predict identical effects to those observed in vitro . Approximately 90% of TFs preferentially bind STRs that need not resemble known motifs, providing a novel cis -regulatory mechanism to target TFs to cognate sites. ### Competing Interest Statement The authors have declared no competing interest." /> <meta name="og-title" property="og:title" content="Short tandem repeats bind transcription factors to tune eukaryotic gene expression" /> <meta name="og-url" property="og:url" content="https://www.biorxiv.org/content/10.1101/2022.05.24.493321v2" /> <meta name="og-site-name" property="og:site_name" content="bioRxiv" /> <meta name="og-description" property="og:description" content="Short tandem repeats (STRs) are enriched in eukaryotic cis -regulatory elements and their polymorphisms alter gene expression, yet how they regulate transcription remains unknown. We find that STRs can modulate transcription factor (TF)-DNA affinities and on rates by up to 70-fold by directly binding TF DNA-binding domains, with energetic impacts approaching or exceeding mutations to consensus sites. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density near motifs to speed target search. Confirming that STRs also impact TF binding in cells, neural networks trained only on in vivo occupancies predict identical effects to those observed in vitro . Approximately 90% of TFs preferentially bind STRs that need not resemble known motifs, providing a novel cis -regulatory mechanism to target TFs to cognate sites. ### Competing Interest Statement The authors have declared no competing interest." /> <meta name="og-type" property="og:type" content="article" /> <meta name="og-image" property="og:image" content="https://www.biorxiv.org/sites/default/files/images/biorxiv_logo_homepage7-5-small.png" /> <meta name="citation_date" content="2022-05-30" /> <link rel="alternate" type="application/vnd.ms-powerpoint" title="Powerpoint" href="/content/10.1101/2022.05.24.493321v2.ppt" /> <meta name="description" content="bioRxiv - the preprint server for biology, operated by Cold Spring Harbor Laboratory, a research and educational institution" /> <meta name="generator" content="Drupal 7 (http://drupal.org)" /> <link rel="canonical" href="https://www.biorxiv.org/content/10.1101/2022.05.24.493321v2" /> <link rel="shortlink" 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id="zone-content" class="zone zone-content clearfix container-30"> <div class="grid-28 suffix-1 prefix-1 region region-content" id="region-content"> <div class="region-inner region-content-inner"> <a id="main-content"></a> <div class="block block-system block-main block-system-main odd block-without-title" id="block-system-main"> <div class="block-inner clearfix"> <div class="content clearfix"> <div class="panel-display panels-960-layout jcore-2col-layout" > <div class="panel-row-wrapper clearfix"> <div class="main-content-wrapper grid-17 suffix-1 alpha"> <div class="panel-panel panel-region-content"> <div class="inside"><div class="panel-pane pane-highwire-article-citation" > <div class="pane-content"> <div class="highwire-article-citation highwire-citation-type-highwire-article node2571106" data-node-nid="2571106" id="node-2571106--2641586532" data-pisa="biorxiv;2022.05.24.493321v2" data-pisa-master="biorxiv;2022.05.24.493321" data-apath="/biorxiv/early/2022/05/30/2022.05.24.493321.atom" data-hw-author-tooltip-instance="highwire_author_tooltip"><div class="highwire-cite highwire-cite-highwire-article highwire-citation-biorxiv-article-top clearfix has-author-tooltip" > <span class="biorxiv-article-type"> New Results </span> <h1 class="highwire-cite-title" id="page-title">Short tandem repeats bind transcription factors to tune eukaryotic gene expression</h1> <div class="highwire-cite-authors" ><span class="highwire-citation-authors"><span class="highwire-citation-author first hw-author-orcid-logo-wrapper" data-delta="0"><a href="http://orcid.org/0000-0001-6018-3556" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Connor A.</span> <span class="nlm-surname">Horton</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="1"><a href="http://orcid.org/0000-0001-8655-8109" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Amr M.</span> <span class="nlm-surname">Alexandari</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="2"><a href="http://orcid.org/0000-0001-5315-7042" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Michael G. B.</span> <span class="nlm-surname">Hayes</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="3"><a href="http://orcid.org/0000-0002-1150-7304" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Emil</span> <span class="nlm-surname">Marklund</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="4"><a href="http://orcid.org/0000-0003-0416-0469" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Julia M.</span> <span class="nlm-surname">Schaepe</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="5"><a href="http://orcid.org/0000-0002-9839-7733" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Arjun K.</span> <span class="nlm-surname">Aditham</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="6"><a href="http://orcid.org/0000-0002-0081-8537" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Nilay</span> <span class="nlm-surname">Shah</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="7"><a href="http://orcid.org/0000-0002-6443-4671" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Avanti</span> <span class="nlm-surname">Shrikumar</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="8"><a href="http://orcid.org/0000-0001-8584-9879" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Ariel</span> <span class="nlm-surname">Afek</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="9"><a href="http://orcid.org/0000-0003-1409-3095" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">William J.</span> <span class="nlm-surname">Greenleaf</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="10"><a href="http://orcid.org/0000-0002-6404-6556" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Raluca</span> <span class="nlm-surname">Gordân</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="11"><a href="http://orcid.org/0000-0002-5172-3335" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Julia</span> <span class="nlm-surname">Zeitlinger</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="12"><a href="http://orcid.org/0000-0003-3084-2287" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Anshul</span> <span class="nlm-surname">Kundaje</span></span>, <span class="highwire-citation-author hw-author-orcid-logo-wrapper" data-delta="13"><a href="http://orcid.org/0000-0002-9505-0638" target="_blank" class="hw-author-orcid-logo link-icon-only link-icon"><span class="hw-icon-orcid hw-icon-color-orcid"></span> <span class="title element-invisible">View ORCID Profile</span></a><span class="nlm-given-names">Polly M.</span> <span class="nlm-surname">Fordyce</span></span></span></div> <div class="highwire-cite-metadata" ><span class="highwire-cite-metadata-doi highwire-cite-metadata"><span class="label">doi:</span> https://doi.org/10.1101/2022.05.24.493321 </span></div> </div> <div id="hw-article-author-popups-node-2571106--2641586532" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">Connor A. Horton </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Genetics, Stanford University</span>, Stanford, CA 94305</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Connor%2BA.%2BHorton%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Horton%20CA&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AConnor%2BA.%2BHorton%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0001-6018-3556" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Connor A. Horton</a></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">Amr M. Alexandari </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>2</span><span class='nlm-institution'>Department of Computer Science, Stanford University</span>, Stanford, CA 94305</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Amr%2BM.%2BAlexandari%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Alexandari%20AM&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AAmr%2BM.%2BAlexandari%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0001-8655-8109" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Amr M. Alexandari</a></li></ul></div><div class="author-tooltip-2"><div class="author-tooltip-name">Michael G. B. Hayes </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Genetics, Stanford University</span>, Stanford, CA 94305</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Michael%2BG.%2BB.%2BHayes%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Hayes%20MG&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AMichael%2BG.%2BB.%2BHayes%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0001-5315-7042" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Michael G. B. Hayes</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">Emil Marklund </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Genetics, Stanford University</span>, Stanford, CA 94305</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Emil%2BMarklund%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Marklund%20E&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AEmil%2BMarklund%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-1150-7304" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Emil Marklund</a></li></ul></div><div class="author-tooltip-4"><div class="author-tooltip-name">Julia M. Schaepe </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>3</span><span class='nlm-institution'>Department of Bioengineering, Stanford University</span>, Stanford, CA 94305</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Julia%2BM.%2BSchaepe%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Schaepe%20JM&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AJulia%2BM.%2BSchaepe%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0003-0416-0469" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Julia M. Schaepe</a></li></ul></div><div class="author-tooltip-5"><div class="author-tooltip-name">Arjun K. Aditham </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>3</span><span class='nlm-institution'>Department of Bioengineering, Stanford University</span>, Stanford, CA 94305</div><div class='author-affiliation'><span class='nlm-sup'>11</span><span class='nlm-institution'>ChEM-H Institute, Stanford University</span>, Stanford, CA 94305</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Arjun%2BK.%2BAditham%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Aditham%20AK&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AArjun%2BK.%2BAditham%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-9839-7733" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Arjun K. Aditham</a></li></ul></div><div class="author-tooltip-6"><div class="author-tooltip-name">Nilay Shah </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>4</span><span class='nlm-institution'>Stowers Institute for Medical Research</span>, Kansas City, MO, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Nilay%2BShah%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Shah%20N&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3ANilay%2BShah%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-0081-8537" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Nilay Shah</a></li></ul></div><div class="author-tooltip-7"><div class="author-tooltip-name">Avanti Shrikumar </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>2</span><span class='nlm-institution'>Department of Computer Science, Stanford University</span>, Stanford, CA 94305</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Avanti%2BShrikumar%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Shrikumar%20A&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AAvanti%2BShrikumar%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-6443-4671" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Avanti Shrikumar</a></li></ul></div><div class="author-tooltip-8"><div class="author-tooltip-name">Ariel Afek </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>6</span><span class='nlm-institution'>Center for Genomic and Computational Biology, Duke University School of Medicine</span>, Durham, NC, <span class='nlm-country'>USA</span></div><div class='author-affiliation'><span class='nlm-sup'>7</span><span class='nlm-institution'>Department of Biostatistics and Bioinformatics, Duke University School of Medicine</span>, Durham, NC, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Ariel%2BAfek%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Afek%20A&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AAriel%2BAfek%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0001-8584-9879" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Ariel Afek</a></li></ul></div><div class="author-tooltip-9"><div class="author-tooltip-name">William J. Greenleaf </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Genetics, Stanford University</span>, Stanford, CA 94305</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=William%2BJ.%2BGreenleaf%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Greenleaf%20WJ&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AWilliam%2BJ.%2BGreenleaf%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0003-1409-3095" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for William J. Greenleaf</a></li></ul></div><div class="author-tooltip-10"><div class="author-tooltip-name">Raluca Gordân </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>6</span><span class='nlm-institution'>Center for Genomic and Computational Biology, Duke University School of Medicine</span>, Durham, NC, <span class='nlm-country'>USA</span></div><div class='author-affiliation'><span class='nlm-sup'>7</span><span class='nlm-institution'>Department of Biostatistics and Bioinformatics, Duke University School of Medicine</span>, Durham, NC, <span class='nlm-country'>USA</span></div><div class='author-affiliation'><span class='nlm-sup'>8</span><span class='nlm-institution'>Department of Computer Science, Duke University</span>, Durham, NC, <span class='nlm-country'>USA</span></div><div class='author-affiliation'><span class='nlm-sup'>9</span><span class='nlm-institution'>Department of Molecular Genetics and Microbiology, Duke University School of Medicine</span>, Durham, NC, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Raluca%2BGord%C3%A2n%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Gord%C3%A2n%20R&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3ARaluca%2BGord%25C3%25A2n%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-6404-6556" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Raluca Gordân</a></li></ul></div><div class="author-tooltip-11"><div class="author-tooltip-name">Julia Zeitlinger </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>4</span><span class='nlm-institution'>Stowers Institute for Medical Research</span>, Kansas City, MO, <span class='nlm-country'>USA</span></div><div class='author-affiliation'><span class='nlm-sup'>10</span><span class='nlm-institution'>The University of Kansas Medical Center</span>, Kansas City, KS, <span class='nlm-country'>USA</span></div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Julia%2BZeitlinger%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Zeitlinger%20J&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AJulia%2BZeitlinger%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0002-5172-3335" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Julia Zeitlinger</a></li></ul></div><div class="author-tooltip-12"><div class="author-tooltip-name">Anshul Kundaje </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Genetics, Stanford University</span>, Stanford, CA 94305</div><div class='author-affiliation'><span class='nlm-sup'>2</span><span class='nlm-institution'>Department of Computer Science, Stanford University</span>, Stanford, CA 94305</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Anshul%2BKundaje%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Kundaje%20A&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3AAnshul%2BKundaje%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link last"><a href="http://orcid.org/0000-0003-3084-2287" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Anshul Kundaje</a></li></ul></div><div class="author-tooltip-13"><div class="author-tooltip-name">Polly M. Fordyce </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span><span class='nlm-institution'>Department of Genetics, Stanford University</span>, Stanford, CA 94305</div><div class='author-affiliation'><span class='nlm-sup'>3</span><span class='nlm-institution'>Department of Bioengineering, Stanford University</span>, Stanford, CA 94305</div><div class='author-affiliation'><span class='nlm-sup'>5</span><span class='nlm-institution'>Stanford Biophysics Program, Stanford University</span>, Stanford, CA 94305</div><div class='author-affiliation'><span class='nlm-sup'>11</span><span class='nlm-institution'>ChEM-H Institute, Stanford University</span>, Stanford, CA 94305</div><div class='author-affiliation'><span class='nlm-sup'>12</span><span class='nlm-institution'>Chan Zuckerberg Biohub</span>, San Francisco, CA 94110</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Polly%2BM.%2BFordyce%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Fordyce%20PM&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3APolly%2BM.%2BFordyce%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-orcid-link"><a href="http://orcid.org/0000-0002-9505-0638" target="_blank" class="" data-icon-position="" data-hide-link-title="0">ORCID record for Polly M. Fordyce</a></li><li class="author-corresp-email-link last"><span>For correspondence: <a href="mailto:pfordyce@stanford.edu" class="" data-icon-position="" data-hide-link-title="0">pfordyce@stanford.edu</a></span></li></ul></div></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-panel-tabs pane-panels-ajax-tab-tabs" > <div class="pane-content"> <div class="item-list"><ul class="tabs inline panels-ajax-tab"><li class="first"><a href="/content/10.1101/2022.05.24.493321v2" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_art" data-target-id="highwire_article_tabs" data-entity-context="node:2571106" data-trigger="" data-url-enabled="1">Abstract</a><a href="/panels_ajax_tab/biorxiv_tab_art/node:2571106/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/2022.05.24.493321v2.full-text" class="panels-ajax-tab-tab" data-panel-name="article_tab_full_text" data-target-id="highwire_article_tabs" data-entity-context="node:2571106" data-trigger="full-text" data-url-enabled="1">Full Text</a><a href="/panels_ajax_tab/article_tab_full_text/node:2571106/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/2022.05.24.493321v2.article-info" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_info" data-target-id="highwire_article_tabs" data-entity-context="node:2571106" data-trigger="article-info" data-url-enabled="1">Info/History</a><a href="/panels_ajax_tab/biorxiv_tab_info/node:2571106/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/2022.05.24.493321v2.article-metrics" class="panels-ajax-tab-tab" data-panel-name="article_tab_metrics" data-target-id="highwire_article_tabs" data-entity-context="node:2571106" data-trigger="article-metrics" data-url-enabled="1">Metrics</a><a href="/panels_ajax_tab/article_tab_metrics/node:2571106/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/2022.05.24.493321v2.supplementary-material" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_data" data-target-id="highwire_article_tabs" data-entity-context="node:2571106" data-trigger="supplementary-material" data-url-enabled="1">Supplementary material</a><a href="/panels_ajax_tab/biorxiv_tab_data/node:2571106/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/10.1101/2022.05.24.493321v2.external-links" class="panels-ajax-tab-tab" data-panel-name="article_tab_data_code" data-target-id="highwire_article_tabs" data-entity-context="node:2571106" data-trigger="external-links" data-url-enabled="1">Data/Code</a><a href="/panels_ajax_tab/article_tab_data_code/node:2571106/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li class="last"><a href="/content/10.1101/2022.05.24.493321v2.full.pdf+html" class="panels-ajax-tab-tab" data-panel-name="biorxiv_tab_pdf" data-target-id="highwire_article_tabs" data-entity-context="node:2571106" data-trigger="full.pdf+html" data-url-enabled="1"><i class="icon-file-alt"></i> Preview PDF</a><a href="/panels_ajax_tab/biorxiv_tab_pdf/node:2571106/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li></ul></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-panel-tabs-container" > <div class="pane-content"> <div data-panels-ajax-tab-preloaded="biorxiv_tab_art" id="panels-ajax-tab-container-highwire_article_tabs" class="panels-ajax-tab-container"><div class="panels-ajax-tab-loading" style ="display:none"><img class="loading" src="https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif" alt="Loading" title="Loading" /></div><div class="panels-ajax-tab-wrap-biorxiv_tab_art"><div class="panel-display panel-1col clearfix" > <div class="panel-panel panel-col"> <div><div class="panel-pane pane-highwire-markup" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" data-highwire-cite-ref-tooltip-instance="highwire_reflinks_tooltip" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article abstract-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2 class="">Abstract</h2><p id="p-4">Short tandem repeats (STRs) are enriched in eukaryotic <em>cis</em>-regulatory elements and their polymorphisms alter gene expression, yet how they regulate transcription remains unknown. We find that STRs can modulate transcription factor (TF)-DNA affinities and on rates by up to 70-fold by directly binding TF DNA-binding domains, with energetic impacts approaching or exceeding mutations to consensus sites. STRs maximize the number of weakly preferred microstates near target sites, thereby increasing TF density near motifs to speed target search. Confirming that STRs also impact TF binding in cells, neural networks trained only on <em>in vivo</em> occupancies predict identical effects to those observed <em>in vitro</em>. Approximately 90% of TFs preferentially bind STRs that need not resemble known motifs, providing a novel <em>cis</em>-regulatory mechanism to target TFs to cognate sites.</p></div><h3>Competing Interest Statement</h3><p id="p-5">The authors have declared no competing interest.</p><div class="section fn-group" id="fn-group-1"><h2>Footnotes</h2><ul><li class="fn-update fn-group-summary-of-updates" id="fn-3"><p id="p-6">This version of the manuscript has been revised to include citations to important prior work.</p></li><li class="fn-dataset fn-group-external-links" id="fn-4"><p id="p-7"> <a href="https://osf.io/gbxhz/">https://osf.io/gbxhz/</a> </p></li><li class="fn-dataset fn-group-external-links" id="fn-5"><p id="p-8"> <a href="https://github.com/FordyceLab/STR_analysis">https://github.com/FordyceLab/STR_analysis</a> </p></li></ul></div><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div> </div> </div> <div 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