Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Nat Commun. 2022 Apr 19;13(1):2042. doi: 10.1038/s41467-022-29625-6.
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.
非编码变异协调跨越超过 100kb 的区域的转录因子 (TF) 结合和染色质标记富集变化。这些在分子上协调一致的区域被称为“可变染色质模块”(VCM)，为调节变异如何塑造复杂性状提供了一个概念框架。为了更好地理解 VCM 形成的分子机制，在这里，我们从机制上剖析了一个与降低慢性淋巴细胞白血病 (CLL) 易感性和疾病进展相关的调节 VCM 的非编码变异。这种常见的种系变异构成了一个 5 碱基对的缺失/插入，通过创建一个 MEF2 结合位点来控制与 AXIN2 基因相关的 VCM 的活性，该结合位点在结合时激活类似超级增强子的调节元件。这会导致跨越 >150kb 的增强子簇处的 TF 结合活性和染色质状态发生巨大变化，同时伴随着细微的长程染色质紧缩和强大的 AXIN2 上调。我们的结果支持这样一种模型，即缺失/插入作为 AXIN2 VCM 激活 TF 成核事件，调节 CLL 病理。
