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与T细胞急性淋巴细胞白血病相关的染色质三维结构
2020-03-29 23:14

纽约大学医学院Aristotelis Tsirigos和Iannis Aifantis研究团队合作在研究中取得进展。他们研究揭示了T细胞急性淋巴细胞白血病的染色质三维(3D)结构。该项研究成果在线发表在2020年3月23日出版的《自然-遗传学》上。

在本研究中,研究人员通过使用原发性人类白血病样本来研究T细胞急性淋巴细胞性白血病(T-ALL)中染色质的3D体系,并研究该体系对药剂的动态响应。原位Hi-C、RNA-seq和CTCF ChIP-seq数据集相匹配系统揭示了T-ALL中拓扑关联域(TAD)内染色质相互作用和TAD隔离边界的广泛差异。该研究确定并着重关注了与CTCF介导隔离缺失相关的TAD“融合”事件,从而使MYC启动子与远端超级增强子直接相互作用。

此外,研究数据还证明靶向致癌信号转导或表观遗传调控的小分子抑制剂可以改变白血病中发现的特定3D相互作用。总体而言,该研究强调了染色质3D结构对人类急性白血病复杂性和动态性质的影响。

据介绍,染色质三维结构的差异可能影响拓扑关联域的完整性,并重建特定的增强子-启动子相互作用,从而影响基因表达并导致人类疾病。

附:英文原文

Title: Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

Author: Andreas Kloetgen, Palaniraja Thandapani, Panagiotis Ntziachristos, Yohana Ghebrechristos, Sofia Nomikou, Charalampos Lazaris, Xufeng Chen, Hai Hu, Sofia Bakogianni, Jingjing Wang, Yi Fu, Francesco Boccalatte, Hua Zhong, Thomas Trimarchi, Yixing Zhu, Pieter Van Vlierberghe, Giorgio G. Inghirami, Timothee Lionnet, Iannis Aifantis, Aristotelis Tsirigos

Issue&Volume: 2020-03-23

Abstract: Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer–promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP–seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD ‘fusion’ event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.

DOI: 10.1038/s41588-020-0602-9

Source: https://www.nature.com/articles/s41588-020-0602-9

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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