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

Llimos, Gerard; Gardeux, Vincent; Koch, Ute; Kribelbauer, Judith F; Hafner, Antonina; Alpern, Daniel; Pezoldt, Joern; ... Deplancke, Bart; + view all (2022) A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation. Nature Communications , 13 (1) , Article 2042. 10.1038/s41467-022-29625-6. Green open access

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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.

Type: Article
Title: A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-022-29625-6
Publisher version: https://doi.org/10.1038/s41467-022-29625-6
Language: English
Additional information: © 2022 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Germ Cells, Chromatin, Humans, Transcription Factors, Gene Expression Regulation, Leukemia, Lymphocytic, Chronic, B-Cell, Enhancer Elements, Genetic
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10147748
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