期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29625-6
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资金
- Swiss Cancer Research foundation [KFS-4275-08-2017]
- Swiss National Science Foundation [310030_197082]
- EPFL
- Research Council of Norway [187615]
- South-Eastern Norway Regional Health Authority
- University of Oslo
- German Cancer Aid project CO-CLL [70113869]
- Associazione Italiana per la Ricerca sul Cancro Foundation, Milan, Italy [21198]
- Swiss National Science Foundation (SNF) [310030_197082] Funding Source: Swiss National Science Foundation (SNF)
This study reveals that a non-coding variant induces transcription factor nucleation through chromatin compaction, leading to up-regulation of the AXIN2 gene and is associated with better prognosis in chronic lymphocytic leukemia.
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.
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