Structural variation cooperates with permissive chromatin to control enhancer hijacking-mediated oncogenic transcription.
Structural variation cooperates with permissive chromatin to control enhancer hijacking-mediated oncogenic transcription.
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DOI：
10.1182/blood.2022017555
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发表时间：
2023-07-27
期刊：
影响因子：
20.3
通讯作者：
Xu, Jian
中科院分区：
文献类型：
--
作者：
Botten, Giovanni A.;Zhang, Yuannyu;Dudnyk, Kseniia;Kim, Yoon Jung;Liu, Xin;Sanders, Jacob T.;Imanci, Aygun;Droin, Nathalie;Cao, Hui;Kaphle, Pranita;Dickerson, Kathryn E.;Kumar, Kirthi R.;Chen, Mingyi;Chen, Weina;Solary, Eric;Ly, Peter;Zhou, Jian;Xu, Jian
我们描述了一个多模式的方法，定量分析的转录和结构的影响所施加的结构变异。增强子劫持与容许染色质合作激活白血病基因组中的致癌转录。涉及增强子劫持的结构变体（SV）可以重新连接染色质拓扑结构，导致人类癌症（包括血液恶性肿瘤）中的癌基因激活;然而，由于缺乏评估其对基因调控和染色质组织影响的工具，增强子劫持功能输出的分子决定因素仍然知之甚少。在这里，我们开发了一种多模式的方法来整合基因组测序，染色体构象，染色质状态，和转录组的改变，定量分析的转录影响和结构重组所施加的白血病基因组中的SV。我们鉴定了已知的和新的致病性SV，包括复发性t（5;14）易位，这种易位导致BCL 11B增强子被劫持，从而在儿科白血病亚型中特异性激活TLX 3。SV劫持的BCL 11 B增强子的表观遗传扰动损害了t（5;14）白血病细胞生长所需的TLX 3转录。通过在同基因白血病细胞中对患者来源的t（5;14）进行CRISPR工程改造，我们发现了一种新的机制，即SV诱导的BCL 11B增强子劫持的转录输出依赖于TLX 3启动子处DNA超甲基化的丧失。我们的研究结果强调了遗传改变和容许染色质之间的合作作为SV介导的癌基因激活的关键决定因素的重要性，并对理解白血病患者表观遗传治疗后的异常基因转录产生影响。因此，利用遗传改变对染色质变异的相互依赖性可能提供新的机会来重新编程基因调控作为人类疾病的靶向干预措施。结构变异（SV）是与正常基因组的大序列差异，通常发生在白血病和其他癌症中。Botten等人描述了一种新的方法，该方法结合了基因组测序、染色质状态和转录特征，以区分驱动白血病发生的致病性SV和非致病性乘客事件。作者将甲基化确定为增强子劫持介导的由SV引起的致癌转录的障碍，并证明了他们的工具和模型（Orca白血病）在原始样本中的适用性。
We describe a multimodal approach for quantitative analysis of transcriptional and structural impacts imposed by structural variants. Enhancer hijacking cooperates with permissive chromatin to activate oncogenic transcription in leukemic genomes. Structural variants (SVs) involving enhancer hijacking can rewire chromatin topologies to cause oncogene activation in human cancers, including hematologic malignancies; however, because of the lack of tools to assess their effects on gene regulation and chromatin organization, the molecular determinants for the functional output of enhancer hijacking remain poorly understood. Here, we developed a multimodal approach to integrate genome sequencing, chromosome conformation, chromatin state, and transcriptomic alteration for quantitative analysis of transcriptional effects and structural reorganization imposed by SVs in leukemic genomes. We identified known and new pathogenic SVs, including recurrent t(5;14) translocations that cause the hijacking of BCL11B enhancers for the allele-specific activation of TLX3 in a subtype of pediatric leukemia. Epigenetic perturbation of SV-hijacked BCL11B enhancers impairs TLX3 transcription, which are required for the growth of t(5;14) leukemia cells. By CRISPR engineering of patient-derived t(5;14) in isogenic leukemia cells, we uncovered a new mechanism whereby the transcriptional output of SV-induced BCL11B enhancer hijacking is dependent on the loss of DNA hypermethylation at the TLX3 promoter. Our results highlight the importance of the cooperation between genetic alteration and permissive chromatin as a critical determinant of SV-mediated oncogene activation, with implications for understanding aberrant gene transcription after epigenetic therapies in patients with leukemia. Hence, leveraging the interdependency of genetic alteration on chromatin variation may provide new opportunities to reprogram gene regulation as targeted interventions in human disease. Structural variants (SVs) are large sequence differences from normal genomes and occur commonly in leukemias and other cancers. Botten et al describe a new approach that combines genome sequencing, chromatin state, and transcriptional signatures to distinguish pathogenic SVs driving leukemogenesis from nonpathogenic passenger events. The authors identify methylation as a barrier to enhancer hijacking–mediated oncogenic transcription arising from SVs and demonstrate the applicability of their tools and model (Orca-Leukemia) in primary samples.
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影响因子：
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