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

Gerard Llimos, Vincent Gardeux, Ute Koch, Judith F. Kribelbauer, Antonina Hafner, Daniel Alpern, Joern Pezoldt, Maria Litovchenko, Julie Russeil, Riccardo Dainese, Riccardo Moia, Abdurraouf Mokhtar Mahmoud, Davide Rossi, Gianluca Gaidano, Christoph Plass, Pavlo Lutsik, Clarissa Gerhauser, Sebastian M. Waszak, Alistair Boettiger, Freddy Radtke and Bart Deplancke ()
Additional contact information
Gerard Llimos: École Polytechnique Fédérale de Lausanne (EPFL)
Vincent Gardeux: École Polytechnique Fédérale de Lausanne (EPFL)
Ute Koch: School of Life Sciences École Polytechnique Fédérale de Lausanne (EPFL)
Judith F. Kribelbauer: École Polytechnique Fédérale de Lausanne (EPFL)
Antonina Hafner: Stanford University
Daniel Alpern: École Polytechnique Fédérale de Lausanne (EPFL)
Joern Pezoldt: École Polytechnique Fédérale de Lausanne (EPFL)
Maria Litovchenko: École Polytechnique Fédérale de Lausanne (EPFL)
Julie Russeil: École Polytechnique Fédérale de Lausanne (EPFL)
Riccardo Dainese: École Polytechnique Fédérale de Lausanne (EPFL)
Riccardo Moia: University of Eastern Piedmont
Abdurraouf Mokhtar Mahmoud: University of Eastern Piedmont
Davide Rossi: 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
Alistair Boettiger: Stanford University
Freddy Radtke: School of Life Sciences École Polytechnique Fédérale de Lausanne (EPFL)
Bart Deplancke: École Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29625-6

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