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A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation

Author

Listed:
  • Gerard Llimos

    (École Polytechnique Fédérale de Lausanne (EPFL)
    Swiss Institute of Bioinformatics)

  • Vincent Gardeux

    (École Polytechnique Fédérale de Lausanne (EPFL)
    Swiss Institute of Bioinformatics)

  • Ute Koch

    (School of Life Sciences École Polytechnique Fédérale de Lausanne (EPFL))

  • Judith F. Kribelbauer

    (École Polytechnique Fédérale de Lausanne (EPFL)
    Swiss Institute of Bioinformatics)

  • Antonina Hafner

    (Stanford University)

  • Daniel Alpern

    (École Polytechnique Fédérale de Lausanne (EPFL)
    Swiss Institute of Bioinformatics)

  • Joern Pezoldt

    (École Polytechnique Fédérale de Lausanne (EPFL)
    Swiss Institute of Bioinformatics)

  • Maria Litovchenko

    (École Polytechnique Fédérale de Lausanne (EPFL)
    Swiss Institute of Bioinformatics
    Cancer Genome Evolution Research Group)

  • Julie Russeil

    (École Polytechnique Fédérale de Lausanne (EPFL))

  • Riccardo Dainese

    (École Polytechnique Fédérale de Lausanne (EPFL)
    Swiss Institute of Bioinformatics)

  • Riccardo Moia

    (University of Eastern Piedmont)

  • Abdurraouf Mokhtar Mahmoud

    (University of Eastern Piedmont)

  • Davide Rossi

    (Università della Svizzera italiana
    Università della Svizzera italiana)

  • Gianluca Gaidano

    (University of Eastern Piedmont)

  • Christoph Plass

    (German Cancer Research Center (DKFZ))

  • Pavlo Lutsik

    (German Cancer Research Center (DKFZ))

  • Clarissa Gerhauser

    (German Cancer Research Center (DKFZ))

  • Sebastian M. Waszak

    (University of Oslo and Oslo University Hospital
    Oslo University Hospital)

  • Alistair Boettiger

    (Stanford University)

  • Freddy Radtke

    (School of Life Sciences École Polytechnique Fédérale de Lausanne (EPFL))

  • Bart Deplancke

    (École Polytechnique Fédérale de Lausanne (EPFL)
    Swiss Institute of Bioinformatics)

Abstract

Non-coding variants coordinate transcription factor (TF) binding and chromatin mark enrichment changes over regions spanning >100 kb. These molecularly coordinated regions are named “variable chromatin modules” (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. To better understand the molecular mechanisms underlying VCM formation, here, we mechanistically dissect a VCM-modulating noncoding variant that is associated with reduced chronic lymphocytic leukemia (CLL) predisposition and disease progression. This common, germline variant constitutes a 5-bp indel that controls the activity of an AXIN2 gene-linked VCM by creating a MEF2 binding site, which, upon binding, activates a super-enhancer-like regulatory element. This triggers a large change in TF binding activity and chromatin state at an enhancer cluster spanning >150 kb, coinciding with subtle, long-range chromatin compaction and robust AXIN2 up-regulation. Our results support a model in which the indel acts as an AXIN2 VCM-activating TF nucleation event, which modulates CLL pathology.

Suggested Citation

  • Gerard Llimos & Vincent Gardeux & Ute Koch & Judith F. Kribelbauer & Antonina Hafner & Daniel Alpern & Joern Pezoldt & Maria Litovchenko & Julie Russeil & Riccardo Dainese & Riccardo Moia & Abdurraouf, 2022. "A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29625-6
    DOI: 10.1038/s41467-022-29625-6
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