PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice
PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice
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DOI：
10.1038/s41467-019-09180-3
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发表时间：
2019-03-29
影响因子：
16.6
通讯作者：
Rad, Roland
中科院分区：
文献类型：
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作者：
Weber, Julia;de la Rosa, Jorge;Rad, Roland
B细胞淋巴瘤是最常见的血液系统恶性肿瘤。虽然测序研究提供了对BCL遗传学的见解，但非突变癌症基因的鉴定仍然具有挑战性。在这里，我们描述了PiggyBac转座子工具和小鼠模型的隐性筛选，并显示其应用研究克隆B细胞淋巴瘤。在全基因组筛选中，我们发现了与不同分子过程相关的BCL基因，包括信号传导、转录调节、染色质调节或RNA代谢。跨物种分析显示了筛选的效率，以查明由非遗传机制改变的人类癌症驱动因素，包括人类BCL中表观遗传学、转录或转录后失调的临床相关基因。我们还描述了一个基于CRISPR/Cas9的BCL功能基因组学体内平台，并验证了发现的基因，如转录因子Rfx 7和染色质调节因子Phip，它们抑制小鼠淋巴瘤的发生。我们的研究对BCL的分子景观提供了全面的见解，并强调了基因组规模筛选为生物学提供信息的力量。
B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.