基因组整合分析发现了儿童白血病和实体肿瘤的长链非编码RNA调控网络。
Integrative genomic analyses identify lncRNA regulatory networks across pediatric leukemias and solid tumors.
发表日期：2023 Aug 16
作者：
Apexa Modi, Gonzalo Lopez, Karina L Conkrite, Chun Su, Tsz Ching Leung, Sathvik Ramanan, Elisabetta Manduchi, Matthew E Johnson, Daphne Cheung, Samantha Gadd, Jinghui Zhang, Malcolm A Smith, Jaime M Guidry Auvil, Soheil Meshinchi, Elizabeth J Perlman, Stephen P Hunger, John M Maris, Andrew D Wells, Struan F A Grant, Sharon J Diskin
来源：
CANCER RESEARCH
摘要：
长链非编码RNA (lncRNA) 在基因调控中起着重要作用，并有助于肿瘤发生。虽然lncRNA表达的癌全体研究已针对成人恶性肿瘤进行，但儿童肿瘤中的lncRNA局面仍然未知。在本研究中，我们整理了1,044例儿童白血病和脑外实体瘤的RNA测序数据，并结合了相应细胞系模型的配对肿瘤全基因组测序和表观遗传学数据，探索了lncRNA表达、调控及其与癌症的关联。在六种儿童肿瘤中鲜活表达了2,657个lncRNA，其中1,142个表达升高与组织类型密切相关。DNA拷贝数改变面比例上相当于蛋白编码基因造成了lncRNA的失调。应用多维框架识别和优先选择影响基因网络的lncRNA，发现在儿童肿瘤中失调的lncRNA与增殖、代谢和DNA损伤特征相关。通过细胞特异性转录因子上游调控的分析，进一步说明了不同组织类型特异性表达和发育相关的lncRNA。这些分析结果的整合为实验验证优先选择了lncRNA，并且对有限神经母细胞瘤特异性的lncRNA-TBX2-AS1进行沉默处理，导致神经母细胞瘤细胞显著增长抑制，从而验证了计算预测结果。综上所述，这些数据全面描述了儿童癌症中lncRNA的调控和功能，为未来的机制研究铺平了道路。
Long non-coding RNAs (lncRNAs) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curated RNA sequencing data for 1,044 pediatric leukemia and extra-cranial solid tumors and integrated paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. A total of 2,657 lncRNAs were robustly expressed across six pediatric cancers, including 1,142 exhibiting histotype-elevated expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multi-dimensional framework to identify and prioritize lncRNAs impacting gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage hallmarks. Analysis of upstream regulation via cell-type specific transcription factors further implicated distinct histotype-elevated and developmental lncRNAs. Integration of these analyses prioritized lncRNAs for experimental validation, and silencing of TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming the computational predictions. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for future mechanistic studies.