A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation

Non-coding variants coordinate transcription factor (TF) binding and chromatin mark enrichment changes over regions spanning >100 kb. We named these molecularly coordinated regions “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 an uncharacterized VCM-modulating non-coding 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 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. Overall design: RNA-seq for the MEC1 CLL cell line with overexpression of AXIN2 or control using a lentiviral infection with the pLV-EF1a-IRES-Puro (#85132, Addgene) vector. ATAC-seq for crispred MEC1 cells to have both rs143348853 genotypes (homozygous ALT and REF). NGS Capture-C for the LCLs GM11931 and GM12282 using the rs143348853 locus as viewpoint.