Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, Massachusetts, 02115, USA.
Dept. of Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Nat Commun. 2020 Dec 9;11(1):6318. doi: 10.1038/s41467-020-20136-w.
Primary effusion lymphoma (PEL) has a very poor prognosis. To evaluate the contributions of enhancers/promoters interactions to PEL cell growth and survival, here we produce H3K27ac HiChIP datasets in PEL cells. This allows us to generate the PEL enhancer connectome, which links enhancers and promoters in PEL genome-wide. We identify more than 8000 genomic interactions in each PEL cell line. By incorporating HiChIP data with H3K27ac ChIP-seq data, we identify interactions between enhancers/enhancers, enhancers/promoters, and promoters/promoters. HiChIP further links PEL super-enhancers to PEL dependency factors MYC, IRF4, MCL1, CCND2, MDM2, and CFLAR. CRISPR knock out of MEF2C and IRF4 significantly reduces MYC and IRF4 super-enhancer H3K27ac signal. Knock out also reduces MYC and IRF4 expression. CRISPRi perturbation of these super-enhancers by tethering transcription repressors to enhancers significantly reduces target gene expression and reduces PEL cell growth. These data provide insights into PEL molecular pathogenesis.
原发性渗出性淋巴瘤（PEL）预后极差。为了评估增强子/启动子相互作用对 PEL 细胞生长和存活的贡献，我们在这里生成了 PEL 细胞中的 H3K27ac HiChIP 数据集。这使我们能够生成 PEL 增强子连接组，该连接组在全基因组范围内连接 PEL 的增强子和启动子。我们在每个 PEL 细胞系中鉴定出超过 8000 个基因组相互作用。通过将 HiChIP 数据与 H3K27ac ChIP-seq 数据相结合，我们鉴定出增强子/增强子、增强子/启动子和启动子/启动子之间的相互作用。HiChIP 进一步将 PEL 超级增强子与 PEL 依赖性因子 MYC、IRF4、MCL1、CCND2、MDM2 和 CFLAR 联系起来。CRISPR 敲除 MEF2C 和 IRF4 显著降低了 MYC 和 IRF4 超级增强子 H3K27ac 信号。敲除还降低了 MYC 和 IRF4 的表达。通过将转录抑制剂连接到增强子上来干扰这些超级增强子，显著降低了靶基因的表达，并降低了 PEL 细胞的生长。这些数据为 PEL 的分子发病机制提供了新的见解。
