Division of Genetics and Epidemiology, Institute of Cancer Research, London, SW7 3RP, UK.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.
Nat Commun. 2019 Aug 9;10(1):3615. doi: 10.1038/s41467-019-11582-2.
Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.
全基因组关联研究为慢性淋巴细胞白血病（CLL）的遗传易感性提供了证据。为了深入了解 CLL 风险的机制，我们分析了多达 486 例原发性 CLL 中 42 个风险位点的染色质可及性、由 H3K27ac 标记的活性调控元件和 DNA 甲基化。我们发现风险位点在 CLL 中显著富集了活性染色质，并有证据表明它们是 CLL 特异性的，或者在正常 B 细胞发育中存在差异调控。然后，我们使用原位启动子捕获 Hi-C 技术，并结合基因表达数据，揭示了风险位点的可能靶基因。候选靶基因富集了与 B 细胞发育相关的途径，如 MYC 和 BCL2 信号通路。在 14 个位点上，分析突出了 63 个变体作为 CLL 风险的可能功能基础。通过整合遗传和表观遗传信息，我们的分析揭示了遗传易感性与 CLL 调控染色质景观之间关系的新见解。
