Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

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, Elisabeth Paietta, Thomas Trimarchi, Yixing Zhu, Pieter Van Vlierberghe, Giorgio G. Inghirami, Timothee Lionnet, Iannis AifantisAristotelis Tsirigos

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)388-400
Number of pages13
JournalNature Genetics
Volume52
Issue number4
DOIs
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Genetics

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    Kloetgen, A., Thandapani, P., Ntziachristos, P., Ghebrechristos, Y., Nomikou, S., Lazaris, C., Chen, X., Hu, H., Bakogianni, S., Wang, J., Fu, Y., Boccalatte, F., Zhong, H., Paietta, E., Trimarchi, T., Zhu, Y., Van Vlierberghe, P., Inghirami, G. G., Lionnet, T., ... Tsirigos, A. (2020). Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia. Nature Genetics, 52(4), 388-400. https://doi.org/10.1038/s41588-020-0602-9