IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29625-6.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29625-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-29625-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    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. 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.
    3. Viechtbauer, Wolfgang, 2010. "Conducting Meta-Analyses in R with the metafor Package," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 36(i03).
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. 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.
    9. 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.
    10. 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.
    11. 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.
    12. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Tara N. Yankee & Sungryong Oh & Emma Wentworth Winchester & Andrea Wilderman & Kelsey Robinson & Tia Gordon & Jill A. Rosenfeld & Jennifer VanOudenhove & Daryl A. Scott & Elizabeth J. Leslie & Justin , 2023. "Integrative analysis of transcriptome dynamics during human craniofacial development identifies candidate disease genes," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    2. Alan Selewa & Kaixuan Luo & Michael Wasney & Linsin Smith & Xiaotong Sun & Chenwei Tang & Heather Eckart & Ivan P. Moskowitz & Anindita Basu & Xin He & Sebastian Pott, 2023. "Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    4. Adrienne Tin & Pascal Schlosser & Pamela R. Matias-Garcia & Chris H. L. Thio & Roby Joehanes & Hongbo Liu & Zhi Yu & Antoine Weihs & Anselm Hoppmann & Franziska Grundner-Culemann & Josine L. Min & Vic, 2021. "Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    5. Andrew D. Grotzinger & Travis T. Mallard & Zhaowen Liu & Jakob Seidlitz & Tian Ge & Jordan W. Smoller, 2023. "Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Andrew D. Grotzinger & Javier de la Fuente & Gail Davies & Michel G. Nivard & Elliot M. Tucker-Drob, 2022. "Transcriptome-wide and stratified genomic structural equation modeling identify neurobiological pathways shared across diverse cognitive traits," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Daniela Klaproth-Andrade & Johannes Hingerl & Yanik Bruns & Nicholas H. Smith & Jakob Träuble & Mathias Wilhelm & Julien Gagneur, 2024. "Deep learning-driven fragment ion series classification enables highly precise and sensitive de novo peptide sequencing," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Sora Yoon & Aditi Chandra & Golnaz Vahedi, 2022. "Stripenn detects architectural stripes from chromatin conformation data using computer vision," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    9. Noah Dukler & Mehreen R. Mughal & Ritika Ramani & Yi-Fei Huang & Adam Siepel, 2022. "Extreme purifying selection against point mutations in the human genome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    10. Christos Miliotis & Yuling Ma & Xanthi-Lida Katopodi & Dimitra Karagkouni & Eleni Kanata & Kaia Mattioli & Nikolas Kalavros & Yered H. Pita-Juárez & Felipe Batalini & Varune R. Ramnarine & Shivani Nan, 2024. "Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    11. C. W. Ryan & S. L. Regan & E. F. Mills & B. T. McGrath & E. Gong & Y. T. Lai & J. B. Sheingold & K. Patel & T. Horowitz & A. Moccia & Y. C. Tsan & A. Srivastava & S. L. Bielas, 2024. "RING1 missense variants reveal sensitivity of DNA damage repair to H2A monoubiquitination dosage during neurogenesis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    12. 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.
    13. Luke Hoberecht & Pirunthan Perampalam & Aaron Lun & Jean-Philippe Fortin, 2022. "A comprehensive Bioconductor ecosystem for the design of CRISPR guide RNAs across nucleases and technologies," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    14. Ting Fu & Kofi Amoah & Tracey W. Chan & Jae Hoon Bahn & Jae-Hyung Lee & Sari Terrazas & Rockie Chong & Sriram Kosuri & Xinshu Xiao, 2024. "Massively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    15. Bart Verkuil & Serpil Atasayi & Marc L Molendijk, 2015. "Workplace Bullying and Mental Health: A Meta-Analysis on Cross-Sectional and Longitudinal Data," PLOS ONE, Public Library of Science, vol. 10(8), pages 1-16, August.
    16. Francesca Pilotto & Ingolf Kühn & Rita Adrian & Renate Alber & Audrey Alignier & Christopher Andrews & Jaana Bäck & Luc Barbaro & Deborah Beaumont & Natalie Beenaerts & Sue Benham & David S. Boukal & , 2020. "Meta-analysis of multidecadal biodiversity trends in Europe," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    17. repec:cup:judgdm:v:15:y:2020:i:6:p:972-988 is not listed on IDEAS
    18. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    19. Jonas Schmidt & Tammo H. A. Bijmolt, 2020. "Accurately measuring willingness to pay for consumer goods: a meta-analysis of the hypothetical bias," Journal of the Academy of Marketing Science, Springer, vol. 48(3), pages 499-518, May.
    20. Mario Herberz & Tobias Brosch & Ulf J. J. Hahnel, 2020. "Kilo what? Default units increase value sensitivity in joint evaluations of energy efficiency," Judgment and Decision Making, Society for Judgment and Decision Making, vol. 15(6), pages 972-988, November.
    21. Piers Steel & Sjoerd Beugelsdijk & Herman Aguinis, 2021. "The anatomy of an award-winning meta-analysis: Recommendations for authors, reviewers, and readers of meta-analytic reviews," Journal of International Business Studies, Palgrave Macmillan;Academy of International Business, vol. 52(1), pages 23-44, February.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29625-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.