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

Chong Wang, Luyao Zhang, Liangru Ke, Weiyue Ding, Sizun Jiang, Difei Li, Yohei Narita, Isabella Hou, Jun Liang, Shijun Li, Haipeng Xiao, Eva Gottwein, Kenneth M. Kaye, Mingxiang Teng () and Bo Zhao ()
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Chong Wang: Brigham and Women’s Hospital and Harvard Medical School
Luyao Zhang: Brigham and Women’s Hospital and Harvard Medical School
Liangru Ke: Brigham and Women’s Hospital and Harvard Medical School
Weiyue Ding: Brigham and Women’s Hospital and Harvard Medical School
Sizun Jiang: Brigham and Women’s Hospital and Harvard Medical School
Difei Li: Brigham and Women’s Hospital and Harvard Medical School
Yohei Narita: Brigham and Women’s Hospital and Harvard Medical School
Isabella Hou: Brigham and Women’s Hospital and Harvard Medical School
Jun Liang: Brigham and Women’s Hospital and Harvard Medical School
Shijun Li: Brigham and Women’s Hospital and Harvard Medical School
Haipeng Xiao: The First Affiliated Hospital, Sun Yat-Sen University
Eva Gottwein: Feinberg School of Medicine, Northwestern University
Kenneth M. Kaye: Brigham and Women’s Hospital and Harvard Medical School
Mingxiang Teng: H. Lee Moffitt Cancer Center and Research Institute
Bo Zhao: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-20136-w

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