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- Title
A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation.
- Authors
Llimos, Gerard; Gardeux, Vincent; Koch, Ute; Kribelbauer, Judith F.; Hafner, Antonina; Alpern, Daniel; Pezoldt, Joern; Litovchenko, Maria; Russeil, Julie; Dainese, Riccardo; Moia, Riccardo; Mahmoud, Abdurraouf Mokhtar; Rossi, Davide; Gaidano, Gianluca; Plass, Christoph; Lutsik, Pavlo; Gerhauser, Clarissa; Waszak, Sebastian M.; Boettiger, Alistair; Radtke, Freddy
- 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. Non-coding variants can regulate transcription factor binding and gene expression at variable chromatin modules. Here, the authors show that a germline variant induces transcription factor nucleation through chromatin compaction leading to AXIN2 up-regulation and is associated to better prognosis in chronic lymphocytic leukaemia.
- Subjects
TRANSCRIPTION factors; CHROMATIN; CHRONIC lymphocytic leukemia; GERM cells; LYMPHOCYTIC leukemia
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-29625-6