Classical views postulate that regulatory variation affects the interaction of transcription factors (TFs) with DNA, which locally affects gene expression and chromatin modifications 3. Although the vast majority (~88–93%) of complex trait- or disease-associated single nucleotide polymorphisms (SNPs) are located outside gene coding regions 1, 2, only a handful of those have been studied at a mechanistic level. Our results support a model in which the indel acts as an AXIN2 VCM-activating TF nucleation event, which modulates CLL pathology.Ī thorough understanding of how genetics contributes to complex traits or disease susceptibility is of great biomedical importance. 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. 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. 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. These molecularly coordinated regions are named “variable chromatin modules” (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. Non-coding variants coordinate transcription factor (TF) binding and chromatin mark enrichment changes over regions spanning >100 kb. Nature Communications volume 13, Article number: 2042 ( 2022) A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation
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