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: Gerard Llimos, Vincent Gardeux, Ute Koch, Judith F Kribelbauer, Antonina Hafner, Daniel Alpern, Joern Pezoldt, Maria Litovchenko, Julie Russeil, Riccardo Dainese, Riccardo Moia, Abdurraouf Mokhtar Mahmoud, Davide Rossi, Gianluca Gaidano, Christoph Plass, Pavlo Lutsik, Clarissa Gerhauser, Sebastian M Waszak, Alistair Boettiger, Freddy Radtke, Bart Deplancke
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 2042 (04 19 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35440565 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Chromatin
• Transcription Factors

Topics

• Chromatin (genetics)
• Enhancer Elements, Genetic (genetics)
• Gene Expression Regulation
• Germ Cells (metabolism)
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics)
• Transcription Factors (metabolism)