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.
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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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