{
  "abstract": "Transcription factors (TFs) are key players in eukaryotic gene regulation, but the DNA binding specificity of many TFs remains unknown. Here, we assayed 284 mostly poorly characterized, putative human TFs using selective microfluidics-based ligand enrichment followed by sequencing (SMiLE-seq), revealing 72 new DNA binding motifs. To investigate whether some of the 158 TFs for which we did not find motifs preferably bind epigenetically modified DNA (i.e. methylated CG dinucleotides), we developed methylation-sensitive SMiLE-seq (meSMiLE-seq). This microfluidic assay simultaneously probes the affinity of a protein to methylated and unmethylated DNA, augmenting the capabilities of the original method to infer methylation-aware binding sites. We assayed 114 TFs with meSMiLE-seq and identified DNA-binding models for 48 proteins, including the known methylation-sensitive binding modes for POU5F1 and RFX5. For 11 TFs, binding to methylated DNA was preferred or resulted in the discovery of alternative, methylation-dependent motifs (e.g. PRDM13), while aversion towards methylated sequences was found for 13 TFs (e.g. USF3). Finally, we uncovered a potential role for ZHX2 as a putative binder of Z-DNA, a left-handed helical DNA structure which is adopted more frequently upon CpG methylation. Altogether, our study significantly expands the human TF codebook by identifying DNA binding motifs for 98 TFs, while providing a versatile platform to quantitatively assay the impact of DNA modifications on TF binding.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland",
    "Swiss Institute of Bioinformatics, Lausanne, Switzerland",
    "Computer Science Institute, Faculty of Mathematics and Physics, Charles University, Prague, Czechia",
    "Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia",
    "Computer Science Institute, Faculty of Mathematics and Physics, Charles University, Prague, Czech Republic",
    "Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic",
    "Donnelly Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada",
    "University of Toronto, Toronto, Ontario, Canada",
    "Chugai Pharmaceutical Co. Ltd, Tokyo, Japan",
    "Alithea Genomics SA, Epalinges, Switzerland",
    "Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada",
    "Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russia",
    "Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia",
    "Institute of Computer Science, Martin Luther University Halle-Wittenberg, Halle, Germany",
    "Department of Medical BioSciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands",
    "Bioinformatics Laboratory, Federal Research Center for Information and Computational Technologies, Novosibirsk, Russia",
    "Department of Computational Biology, Sirius University of Science and Technology, Sirius, Russia",
    "Moscow Center for Advanced Studies, Moscow, Russia",
    "Bioinformatics Competence Center, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland",
    "Bioinformatics Competence Center, Université de Lausanne, Lausanne, Switzerland",
    "Biosoft.Ru LLC, Novosibirsk, Russia",
    "Life Improvement by Future Technologies (LIFT) Center, Moscow, Russia",
    "Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia",
    "Max Planck Institute of Biochemistry, Planegg, Germany",
    "Altius Institute for Biomedical Sciences, Seattle, WA, USA",
    "TUD Dresden University of Technology, Center for Molecular and Cellular Bioengineering (CMCB), Biotechnologisches Zentrum (BIOTEC), Dresden, Germany",
    "McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada",
    "Memorial Sloan Kettering Cancer Center, Rockefeller Research Laboratories, New York, NY, USA",
    "Cincinnati Children’s Hospital, Cincinnati, OH, USA",
    "Institute of Biochemistry and Genetics, Ufa Federal Research Centre of Russian Academy of Sciences, Ufa, Russia",
    "Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA",
    "Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands",
    "Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. bart.deplancke@epfl.ch",
    "Swiss Institute of Bioinformatics, Lausanne, Switzerland. bart.deplancke@epfl.ch"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 59,
  "authors": [
    {
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        0,
        1
      ],
      "name": "Antoni J. Gralak",
      "orcid": "0009-0007-1086-6165"
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    {
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        2,
        3,
        4,
        5
      ],
      "name": "Kateřina Faltejsková",
      "orcid": "0000-0001-7390-8077"
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    {
      "affs": [
        6,
        7
      ],
      "name": "Ally W. H. Yang",
      "orcid": "0000-0002-8678-0946"
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        0
      ],
      "name": "Clemence Steiner"
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      "name": "Julie Russeil",
      "orcid": "0000-0002-0880-9483"
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      ],
      "name": "Nadia Grenningloh",
      "orcid": "0009-0008-8321-8852"
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      "name": "Sachi Inukai",
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      "name": "Mustafa Demir"
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      "name": "Riccardo Dainese",
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      "name": "C. C. Owen"
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      "name": "Eugenia V. Pankevich",
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      "name": "Philipp Bücher",
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      "name": "Oriol Fornés",
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      "name": "Jan Grau",
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      "name": "Ivo Große",
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      "name": "Arttu Jolma",
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      "name": "Fedor A. Kolpakov"
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      "name": "Vsevolod J. Makeev",
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      "name": "Mihai Albu",
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      "name": "Marjan Barazandeh",
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      "name": "Alexander V. Brechalov",
      "orcid": "0000-0003-0540-4517"
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      "name": "Zhenfeng Deng",
      "orcid": "0009-0006-3881-9312"
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      "affs": [
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      "name": "Ali Fathi",
      "orcid": "0009-0007-1441-9653"
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    {
      "affs": [
        6
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      "name": "Chun Hu"
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    {
      "affs": [
        6
      ],
      "name": "Samuel A. Lambert",
      "orcid": "0000-0001-8222-008X"
    },
    {
      "affs": [
        6
      ],
      "name": "Kaitlin U. Laverty",
      "orcid": "0009-0004-4341-4665"
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    {
      "affs": [
        6
      ],
      "name": "Zain M. Patel"
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    {
      "affs": [
        6
      ],
      "name": "Sara E. Pour",
      "orcid": "0009-0009-6201-1921"
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    {
      "affs": [
        6
      ],
      "name": "Rozita Razavi",
      "orcid": "0009-0000-5466-6519"
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    {
      "affs": [
        6
      ],
      "name": "Mikhail Salnikov"
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    {
      "affs": [
        6
      ],
      "name": "Isaac Yellan",
      "orcid": "0000-0001-6622-1189"
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    {
      "affs": [
        6
      ],
      "name": "Hong Zheng"
    },
    {
      "affs": [
        11
      ],
      "name": "Georgy Meshcheryakov"
    },
    {
      "affs": [
        18,
        19
      ],
      "name": "Giovanna Ambrosini",
      "orcid": "0000-0003-1294-6541"
    },
    {
      "affs": [
        13
      ],
      "name": "Marie-Luise Plescher",
      "orcid": "0009-0006-6163-9782"
    },
    {
      "affs": [
        16
      ],
      "name": "Semyon K. Kolmykov",
      "orcid": "0000-0002-9259-0495"
    },
    {
      "affs": [
        20
      ],
      "name": "Ivan Yevshin"
    },
    {
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        11,
        21
      ],
      "name": "Nikita Gryzunov",
      "orcid": "0009-0000-0782-8650"
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        11
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      "name": "Ivan Kozin",
      "orcid": "0009-0009-4603-8550"
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      "affs": [
        22
      ],
      "name": "Mikhail Nikonov"
    },
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        22
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      "name": "Vladimir Nozdrin",
      "orcid": "0009-0004-3053-1387"
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        22
      ],
      "name": "Arsenii O. Zinkevich",
      "orcid": "0000-0001-9450-4629"
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      "name": "Pavel Kravchenko",
      "orcid": "0000-0002-5751-7129"
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        12
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      "name": "Sergey Abramov",
      "orcid": "0000-0002-3334-5334"
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        24,
        12
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      "name": "Alexandr Boytsov",
      "orcid": "0000-0002-2712-8368"
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        17,
        12
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      "name": "Vasilii Kamenets"
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    {
      "affs": [
        12
      ],
      "name": "Dmitry Penzar"
    },
    {
      "affs": [
        25
      ],
      "name": "Anton Vlasov",
      "orcid": "0000-0001-8558-9763"
    },
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      "affs": [
        12
      ],
      "name": "Ilya E. Vorontsov",
      "orcid": "0000-0001-8888-0804"
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    {
      "affs": [
        26
      ],
      "name": "Aldo Hernández-Corchado",
      "orcid": "0000-0003-0682-3959"
    },
    {
      "affs": [
        26
      ],
      "name": "Hamed Shateri Najafabadi",
      "orcid": "0000-0003-2735-4231"
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    {
      "affs": [
        27
      ],
      "name": "Quaid Morris"
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        28
      ],
      "name": "Xiaoting Chen",
      "orcid": "0000-0002-3782-3962"
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    {
      "affs": [
        28
      ],
      "name": "Matthew T. Weirauch",
      "orcid": "0000-0001-7977-9122"
    },
    {
      "affs": [
        6
      ],
      "name": "Timothy R. Hughes",
      "orcid": "0000-0002-8721-4719"
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    {
      "affs": [
        29,
        11,
        12
      ],
      "name": "Ivan V. Kulakovskiy",
      "orcid": "0000-0002-6554-8128"
    },
    {
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        30,
        0,
        1
      ],
      "name": "Judith F. Kribelbauer-Swietek",
      "orcid": "0000-0002-8072-7773"
    },
    {
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        31,
        0,
        1
      ],
      "name": "Guido van Mierlo",
      "orcid": "0000-0001-5883-0339"
    },
    {
      "affs": [
        32,
        33
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      "name": "Bart Deplancke",
      "orcid": "0000-0001-9935-843X"
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  ],
  "bibtex": "https://research.draconitic.com/paper/dxnyr3sp3adp1.bib",
  "cited_by": 7,
  "doi": "10.1038/s41467-026-71387-y",
  "fulltext_url": null,
  "id": "dxnyr3sp3adp1",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://doi.org/10.1038/s41467-026-71387-y",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "openalex",
      "1312|Genomics and Chromatin Dynamics"
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  "pdf_url": "https://www.nature.com/articles/s41467-026-71387-y.pdf",
  "pmcid": "PMC11601298",
  "pmid": "39605503",
  "published": "2026-08-05",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/dxnyr3sp3adp1.ris",
  "sources": [
    {
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      "native_id": "W4404280684",
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      "url": "https://doi.org/10.1038/s41467-026-71387-y"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics and Chromatin Dynamics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Identification of methylation-sensitive human transcription factors using meSMiLE-seq",
  "title_text": "Identification of methylation-sensitive human transcription factors using meSMiLE-seq",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T13:20:30Z",
  "url": "https://research.draconitic.com/paper/dxnyr3sp3adp1",
  "venue": "Nature Communications",
  "versions": []
}