Liang Jun, Zhou Hufeng, Gerdt Catherine, Tan Min, Colson Tyler, Kaye Kenneth M, Kieff Elliott, Zhao Bo
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Program in Virology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2016 Dec 6;113(49):14121-14126. doi: 10.1073/pnas.1616697113. Epub 2016 Nov 18.
Epstein-Barr virus (EBV) super-enhancers (ESEs) are essential for lymphoblastoid cell (LCL) growth and survival. Reanalyses of LCL global run-on sequencing (Gro-seq) data found abundant enhancer RNAs (eRNAs) being transcribed at ESEs. Inactivation of ESE components, EBV nuclear antigen 2 (EBNA2) and bromodomain-containing protein 4 (BRD4), significantly decreased eRNAs at ESEs -428 and -525 kb upstream of the MYC oncogene transcription start site (TSS). shRNA knockdown of the MYC -428 and -525 ESE eRNA caused LCL growth arrest and reduced cell growth. Furthermore, MYC ESE eRNA knockdown also significantly reduced MYC expression, ESE H3K27ac signals, and MYC ESEs looping to MYC TSS. These data indicate that ESE eRNAs strongly affect cell gene expression and enable LCL growth.
爱泼斯坦-巴尔病毒(EBV)超级增强子(ESEs)对淋巴母细胞(LCL)的生长和存活至关重要。对LCL全基因组连续转录测序(Gro-seq)数据的重新分析发现,在ESEs处有大量增强子RNA(eRNAs)被转录。ESE成分,即EBV核抗原2(EBNA2)和含溴结构域蛋白4(BRD4)的失活,显著降低了位于原癌基因MYC转录起始位点(TSS)上游-428和-525 kb处ESEs的eRNAs。通过短发夹RNA(shRNA)敲低MYC的-428和-525 ESE eRNA导致LCL生长停滞并降低细胞生长。此外,敲低MYC ESE eRNA也显著降低了MYC表达、ESE组蛋白H3赖氨酸27乙酰化(H3K27ac)信号以及MYC ESEs与MYC TSS的环化。这些数据表明,ESE eRNAs强烈影响细胞基因表达并促进LCL生长。