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Genomics and gene therapy

CTCF-mediated genome organization and leukemogenesis

Abstract

Recent technological advancements and genome-wide studies provide compelling evidence that dynamic chromatin interaction and three-dimensional genome organization in nuclei play an important role in regulating gene expression. Mammalian genomes consist of many small functional domains termed topologically associated domains (TADs), many of them organized by CCCTC-binding factor (CTCF) and the cohesion complex. Changes in genome TADs might result in inappropriate promoter/enhancer communications leading to activation of oncogenes or suppression of tumor suppressors. During normal hematopoiesis and leukemogenesis, genome structure alters considerably to facilitate normal and malignant hematopoiesis, respectively. Delineating theses normal and abnormal processes will evolve our understanding of disease pathogenesis and development of potential treatment strategies. This review highlights the role of CTCF and its associated protein complexes in three-dimensional genome organization in development and leukemogenesis, as well as the roles of CTCF boundary defined TAD in transcription regulation. We further explore the function of chromatin modulators, such as CTCF, cohesin, and long noncoding RNAs (lncRNAs) in chromosomal interactions and hematopoietic genome organization. Finally, we focus on the implication of 3D genome alteration in the pathogenesis of leukemia and provide a scientific basis for targeted intervention.

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Fig. 1: The schematic presentation of chicken β-globin locus, in which the first vertebrate chromatin insulator, cHS4, was identified.
Fig. 2: CTCF-mediated 3D genome organization regulates developmental specific transcription program.
Fig. 3: The model depicts that cell type specific formation of TADs/sub-TADs at the TAL1 locus modulates expression of TAL1 oncogene.

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Acknowledgements

We thank our colleague in the SH and YQ Labs for their comments on this paper. The authors also thank Rachael Mills for editing the paper. This work was supported by the grants from the National Institute of Health (R01DK110108, R01CA204044, R01HL141950 to SH; R01HL144712 to YQ) and the Four Diamonds Fund (SH).

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YQ and SH both conceived the idea and wrote the paper.

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Correspondence to Yi Qiu or Suming Huang.

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Qiu, Y., Huang, S. CTCF-mediated genome organization and leukemogenesis. Leukemia 34, 2295–2304 (2020). https://doi.org/10.1038/s41375-020-0906-x

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