Llimos, GerardGardeux, VincentKoch, UteKribelbauer, Judith F.Hafner, AntoninaAlpern, DanielPezoldt, JoernLitovchenko, MariaRusseil, JulieDainese, RiccardoMoia, RiccardoMahmoud, Abdurraouf MokhtarRossi, DavideGaidano, GianlucaPlass, ChristophLutsik, PavloGerhauser, ClarissaWaszak, Sebastian M.Boettiger, AlistairRadtke, FreddyDeplancke, Bart2022-05-232022-05-232022-05-232022-04-1910.1038/s41467-022-29625-6https://infoscience.epfl.ch/handle/20.500.14299/188131WOS:000784997300052Non-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.Multidisciplinary SciencesScience & Technology - Other Topicstext::journal::journal article::research article