美国哥伦比亚大学Uttiya Basu等研究人员合作发现，非编码突变引起超级增强子重定向，导致B细胞淋巴瘤进展过程中蛋白质合成失调。相关论文于2023年12月4日在线发表于国际学术期刊《自然—遗传学》。

研究人员对代表滤泡性淋巴瘤向伴有MYC和BCL2重排的高级别B细胞淋巴瘤（双打击淋巴瘤）转化的纵向肿瘤对进行全基因组测序，发现了淋巴瘤进展过程中获得的编码和非编码基因组改变。这些与转化相关的改变中，有许多反复出现在拓扑关联域驻留调控DNA元件上，包括位于B细胞非霍奇金淋巴瘤中H3K27ac超级增强子簇内的H3K4me3启动子标记。其中一个被发现在转化时反复发生改变的区域与影响PAX5/ZCCHC7基因对表达的超级增强子重叠。

ZCCHC7编码Trf4/5-Air1/2-Mtr4多腺苷酸化样复合物的一个亚基，在淋巴瘤转化时表现出拷贝数增殖、染色体易位和增强子重定向介导的转录上调。因此，淋巴瘤细胞通过改变非编码5.8S核糖体RNA的加工过程而表现出核仁失调。研究人员发现，淋巴瘤发展过程中获得的非编码突变会影响非编码rRNA的加工，从而重塑蛋白质合成，导致淋巴瘤蛋白质组发生致癌变化。

附：英文原文

Title: Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression

Author: Leeman-Neill, Rebecca J., Song, Dong, Bizarro, Jonathan, Wacheul, Ludivine, Rothschild, Gerson, Singh, Sameer, Yang, Yang, Sarode, Aditya Y., Gollapalli, Kishore, Wu, Lijing, Zhang, Wanwei, Chen, Yiyun, Lauring, Max C., Whisenant, D. Eric, Bhavsar, Shweta, Lim, Junghyun, Swerdlow, Steven H., Bhagat, Govind, Zhao, Qian, Berchowitz, Luke E., Lafontaine, Denis L. J., Wang, Jiguang, Basu, Uttiya

Issue&Volume: 2023-12-04

Abstract: Whole-genome sequencing of longitudinal tumor pairs representing transformation of follicular lymphoma to high-grade B cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) identified coding and noncoding genomic alterations acquired during lymphoma progression. Many of these transformation-associated alterations recurrently and focally occur at topologically associating domain resident regulatory DNA elements, including H3K4me3 promoter marks located within H3K27ac super-enhancer clusters in B cell non-Hodgkin lymphoma. One region found to undergo recurrent alteration upon transformation overlaps a super-enhancer affecting the expression of the PAX5/ZCCHC7 gene pair. ZCCHC7 encodes a subunit of the Trf4/5-Air1/2-Mtr4 polyadenylation-like complex and demonstrated copy number gain, chromosomal translocation and enhancer retargeting-mediated transcriptional upregulation upon lymphoma transformation. Consequently, lymphoma cells demonstrate nucleolar dysregulation via altered noncoding 5.8S ribosomal RNA processing. We find that a noncoding mutation acquired during lymphoma progression affects noncoding rRNA processing, thereby rewiring protein synthesis leading to oncogenic changes in the lymphoma proteome.

DOI: 10.1038/s41588-023-01561-1

Source: https://www.nature.com/articles/s41588-023-01561-1