TY - JOUR
T1 - Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia
AU - Kloetgen, Andreas
AU - Thandapani, Palaniraja
AU - Ntziachristos, Panagiotis
AU - Ghebrechristos, Yohana
AU - Nomikou, Sofia
AU - Lazaris, Charalampos
AU - Chen, Xufeng
AU - Hu, Hai
AU - Bakogianni, Sofia
AU - Wang, Jingjing
AU - Fu, Yi
AU - Boccalatte, Francesco
AU - Zhong, Hua
AU - Paietta, Elisabeth
AU - Trimarchi, Thomas
AU - Zhu, Yixing
AU - Van Vlierberghe, Pieter
AU - Inghirami, Giorgio G.
AU - Lionnet, Timothee
AU - Aifantis, Iannis
AU - Tsirigos, Aristotelis
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41588-020-0602-9
DO - 10.1038/s41588-020-0602-9
M3 - Article
C2 - 32203470
AN - SCOPUS:85082197331
SN - 1061-4036
VL - 52
SP - 388
EP - 400
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -