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BANP opens chromatin and activates CpG-island-regulated genes

Author

Listed:
  • Ralph S. Grand

    (Friedrich Miescher Institute for Biomedical Research)

  • Lukas Burger

    (Friedrich Miescher Institute for Biomedical Research
    Swiss Institute of Bioinformatics)

  • Cathrin Gräwe

    (Radboud University Nijmegen)

  • Alicia K. Michael

    (Friedrich Miescher Institute for Biomedical Research)

  • Luke Isbel

    (Friedrich Miescher Institute for Biomedical Research
    University of New South Wales)

  • Daniel Hess

    (Friedrich Miescher Institute for Biomedical Research)

  • Leslie Hoerner

    (Friedrich Miescher Institute for Biomedical Research)

  • Vytautas Iesmantavicius

    (Friedrich Miescher Institute for Biomedical Research)

  • Sevi Durdu

    (Friedrich Miescher Institute for Biomedical Research)

  • Marco Pregnolato

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Arnaud R. Krebs

    (Friedrich Miescher Institute for Biomedical Research
    Genome Biology Unit, European Molecular Biology Laboratory)

  • Sébastien A. Smallwood

    (Friedrich Miescher Institute for Biomedical Research)

  • Nicolas Thomä

    (Friedrich Miescher Institute for Biomedical Research)

  • Michiel Vermeulen

    (Radboud University Nijmegen)

  • Dirk Schübeler

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

Abstract

The majority of gene transcripts generated by RNA polymerase II in mammalian genomes initiate at CpG island (CGI) promoters1,2, yet our understanding of their regulation remains limited. This is in part due to the incomplete information that we have on transcription factors, their DNA-binding motifs and which genomic binding sites are functional in any given cell type3–5. In addition, there are orphan motifs without known binders, such as the CGCG element, which is associated with highly expressed genes across human tissues and enriched near the transcription start site of a subset of CGI promoters6–8. Here we combine single-molecule footprinting with interaction proteomics to identify BTG3-associated nuclear protein (BANP) as the transcription factor that binds this element in the mouse and human genome. We show that BANP is a strong CGI activator that controls essential metabolic genes in pluripotent stem and terminally differentiated neuronal cells. BANP binding is repelled by DNA methylation of its motif in vitro and in vivo, which epigenetically restricts most binding to CGIs and accounts for differential binding at aberrantly methylated CGI promoters in cancer cells. Upon binding to an unmethylated motif, BANP opens chromatin and phases nucleosomes. These findings establish BANP as a critical activator of a set of essential genes and suggest a model in which the activity of CGI promoters relies on methylation-sensitive transcription factors that are capable of chromatin opening.

Suggested Citation

  • Ralph S. Grand & Lukas Burger & Cathrin Gräwe & Alicia K. Michael & Luke Isbel & Daniel Hess & Leslie Hoerner & Vytautas Iesmantavicius & Sevi Durdu & Marco Pregnolato & Arnaud R. Krebs & Sébastien A., 2021. "BANP opens chromatin and activates CpG-island-regulated genes," Nature, Nature, vol. 596(7870), pages 133-137, August.
  • Handle: RePEc:nat:nature:v:596:y:2021:i:7870:d:10.1038_s41586-021-03689-8
    DOI: 10.1038/s41586-021-03689-8
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    Cited by:

    1. Teresa Rummel & Lygeri Sakellaridi & Florian Erhard, 2023. "grandR: a comprehensive package for nucleotide conversion RNA-seq data analysis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Yihao Lu & Meritxell Oliva & Brandon L. Pierce & Jin Liu & Lin S. Chen, 2024. "Integrative cross-omics and cross-context analysis elucidates molecular links underlying genetic effects on complex traits," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. 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.

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