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

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.

Authors

Llimos G  •  Gardeux V  •  Koch U  •  Kribelbauer JF  •  Hafner A  •  Alpern D  •  Pezoldt J  •  Litovchenko M  •  Russeil J  •  Dainese R  •  Moia R  •  Mahmoud AM  •  Rossi D  •  Gaidano G  •  Plass C  •  Lutsik P  •  Gerhauser C  •  Waszak SM  •  Boettiger A  •  Radtke F  •  Deplancke B

Link

https://www.ncbi.nlm.nih.gov/pubmed/35440565