Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

• Published in: Nature communications Vol. 11; no. 1; pp. 6318 - 13
• Main Authors: Wang, Chong, Zhang, Luyao, Ke, Liangru, Ding, Weiyue, Jiang, Sizun, Li, Difei, Narita, Yohei, Hou, Isabella, Liang, Jun, Li, Shijun, Xiao, Haipeng, Gottwein, Eva, Kaye, Kenneth M., Teng, Mingxiang, Zhao, Bo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.12.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 38/1; 38/43; 38/61; 38/77; 38/88; 45; 45/15; 45/22; 631/1647/2210/2211; 631/337/100/101; 631/337/100/102; 631/337/176/2016; 64; 96; Cell growth; Cell Line, Tumor; Cell Proliferation - genetics; Cell survival; Chromatin Immunoprecipitation Sequencing; CRISPR; Dependence; Effusion; Enhancer Elements, Genetic - genetics; Enhancers; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Gene Regulatory Networks; Genomes; Herpesvirus 8, Human - pathogenicity; Histones - genetics; Humanities and Social Sciences; Humans; Interferon regulatory factor 4; Interferon Regulatory Factors - genetics; Links; Lymphoma; Lymphoma, Primary Effusion - genetics; Lymphoma, Primary Effusion - pathology; Lymphoma, Primary Effusion - virology; Mcl-1 protein; MDM2 protein; Medical prognosis; MEF2 Transcription Factors - genetics; MEF2 Transcription Factors - metabolism; multidisciplinary; Myc protein; Pathogenesis; Perturbation; Primary effusion lymphoma; Prognosis; Promoter Regions, Genetic - genetics; Promoters; Proto-Oncogene Proteins c-myc - genetics; Repressors; Science; Science (multidisciplinary); Tethering; Transcription factors
• ISSN: 2041-1723; 2041-1723
• 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. Primary effusion lymphoma (PEL) has a very poor prognosis. Here, the authors perform H3K27ac HiChIP in PEL cells and generate the PEL enhancer connectome, linking enhancers and promoters in PEL, as well as super-enhancers to dependency factors.