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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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    as
    1. Feng Zhou & Yu Lu & Scott B. Ficarro & Guillaume Adelmant & Wenyu Jiang & C. John Luckey & Jarrod A. Marto, 2013. "Genome-scale proteome quantification by DEEP SEQ mass spectrometry," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    2. Xose S. Puente & Silvia Beà & Rafael Valdés-Mas & Neus Villamor & Jesús Gutiérrez-Abril & José I. Martín-Subero & Marta Munar & Carlota Rubio-Pérez & Pedro Jares & Marta Aymerich & Tycho Baumann & Ren, 2015. "Non-coding recurrent mutations in chronic lymphocytic leukaemia," Nature, Nature, vol. 526(7574), pages 519-524, October.
    3. Michael Lawrence & Wolfgang Huber & Hervé Pagès & Patrick Aboyoun & Marc Carlson & Robert Gentleman & Martin T Morgan & Vincent J Carey, 2013. "Software for Computing and Annotating Genomic Ranges," PLOS Computational Biology, Public Library of Science, vol. 9(8), pages 1-10, August.
    4. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    5. Melina Claussnitzer & Judy H. Cho & Rory Collins & Nancy J. Cox & Emmanouil T. Dermitzakis & Matthew E. Hurles & Sekar Kathiresan & Eimear E. Kenny & Cecilia M. Lindgren & Daniel G. MacArthur & Kathry, 2020. "A brief history of human disease genetics," Nature, Nature, vol. 577(7789), pages 179-189, January.
    6. Anshul Kundaje & Wouter Meuleman & Jason Ernst & Misha Bilenky & Angela Yen & Alireza Heravi-Moussavi & Pouya Kheradpour & Zhizhuo Zhang & Jianrong Wang & Michael J. Ziller & Viren Amin & John W. Whit, 2015. "Integrative analysis of 111 reference human epigenomes," Nature, Nature, vol. 518(7539), pages 317-330, February.
    7. Leslie J. Mateo & Sedona E. Murphy & Antonina Hafner & Isaac S. Cinquini & Carly A. Walker & Alistair N. Boettiger, 2019. "Visualizing DNA folding and RNA in embryos at single-cell resolution," Nature, Nature, vol. 568(7750), pages 49-54, April.
    8. Viechtbauer, Wolfgang, 2010. "Conducting Meta-Analyses in R with the metafor Package," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 36(i03).
    9. Charles Y. Lin & Serap Erkek & Yiai Tong & Linlin Yin & Alexander J. Federation & Marc Zapatka & Parthiv Haldipur & Daisuke Kawauchi & Thomas Risch & Hans-Jörg Warnatz & Barbara C. Worst & Bensheng Ju, 2016. "Active medulloblastoma enhancers reveal subgroup-specific cellular origins," Nature, Nature, vol. 530(7588), pages 57-62, February.
    10. Alistair N. Boettiger & Bogdan Bintu & Jeffrey R. Moffitt & Siyuan Wang & Brian J. Beliveau & Geoffrey Fudenberg & Maxim Imakaev & Leonid A. Mirny & Chao-ting Wu & Xiaowei Zhuang, 2016. "Super-resolution imaging reveals distinct chromatin folding for different epigenetic states," Nature, Nature, vol. 529(7586), pages 418-422, January.
    11. Scott Smemo & Juan J. Tena & Kyoung-Han Kim & Eric R. Gamazon & Noboru J. Sakabe & Carlos Gómez-Marín & Ivy Aneas & Flavia L. Credidio & Débora R. Sobreira & Nora F. Wasserman & Ju Hee Lee & Vijitha P, 2014. "Obesity-associated variants within FTO form long-range functional connections with IRX3," Nature, Nature, vol. 507(7492), pages 371-375, March.
    12. Helen E. Speedy & Renée Beekman & Vicente Chapaprieta & Giulia Orlando & Philip J. Law & David Martín-García & Jesús Gutiérrez-Abril & Daniel Catovsky & Sílvia Beà & Guillem Clot & Montserrat Puiggròs, 2019. "Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
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