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Characterization of functional transposable element enhancers in acute myeloid leukemia

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Abstract

Transposable elements (TEs) have been shown to have important gene regulatory functions and their alteration could lead to disease phenotypes. Acute myeloid leukemia (AML) develops as a consequence of a series of genetic changes in hematopoietic precursor cells, including mutations in epigenetic factors. Here, we set out to study the gene regulatory role of TEs in AML. We first explored the epigenetic landscape of TEs in AML patients using ATAC-seq data. We show that a large number of TEs in general, and more specifically mammalian-wide interspersed repeats (MIRs), are more enriched in AML cells than in normal blood cells. We obtained a similar finding when analyzing histone modification data in AML patients. Gene Ontology enrichment analysis showed that genes near MIRs in open chromatin regions are involved in leukemogenesis. To functionally validate their regulatory role, we selected 19 MIR regions in AML cells, and tested them for enhancer activity in an AML cell line (Kasumi-1) and a chronic myeloid leukemia (CML) cell line (K562); the results revealed several MIRs to be functional enhancers. Taken together, our results suggest that TEs are potentially involved in myeloid leukemogenesis and highlight these sequences as potential candidates harboring AML-associated variation.

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Data availability

Data that support the findings of this study were all published by others; a summary of the used data is presented in Table S6 in Supporting Information.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (91749205, 91329302, and 31210103916), Ministry of Science and Technology of China (2015CB964803 and 2016YFE0108700), and a Max Planck fellowship to J. D.J.H. This work was also supported by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (1R01CA197139), NHGRI (1UM1HG009408), and the National Health Lung and Blood Institute (1R01HL138424) to NA. R.S.H is a Recipient of a Fellowship Scholarship from the American Healthcare Professionals and Friends for Medicine in Israel. This study made use of data generated by the Blueprint Consortium.

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  1. Contributed equally to this work

Authors and Affiliations

  1. CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Yingying Zeng, Yaqiang Cao, Denghui Liu, Xiaoli Zhang & Jing-Dong J. Han

  2. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, 94158, USA

    Rivka Sukenik Halevy, Picard Nguyen & Nadav Ahituv

  3. Institute for Human Genetics, University of California San Francisco, San Francisco, 94143, USA

    Rivka Sukenik Halevy, Picard Nguyen & Nadav Ahituv

  4. Sackler School of Medicine, Tel-Aviv University, Tel Aviv, 6997801, Israel

    Rivka Sukenik Halevy

  5. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology, Peking University, Beijing, 100871, China

    Jing-Dong J. Han

Authors
  1. Yingying Zeng
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  2. Yaqiang Cao
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  3. Rivka Sukenik Halevy
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  4. Picard Nguyen
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  5. Denghui Liu
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  6. Xiaoli Zhang
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  7. Nadav Ahituv
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  8. Jing-Dong J. Han
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Corresponding authors

Correspondence to Nadav Ahituv or Jing-Dong J. Han.

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Compliance and ethics The author(s) declare that they have no conflict of interest.

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Zeng, Y., Cao, Y., Halevy, R.S. et al. Characterization of functional transposable element enhancers in acute myeloid leukemia. Sci. China Life Sci. 63, 675–687 (2020). https://doi.org/10.1007/s11427-019-1574-x

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  • DOI: https://doi.org/10.1007/s11427-019-1574-x

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