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Subtype-specific 3D genome alteration in acute myeloid leukaemia

Author

Listed:
  • Jie Xu

    (Northwestern University
    Penn State University)

  • Fan Song

    (Northwestern University
    Penn State University)

  • Huijue Lyu

    (Northwestern University)

  • Mikoto Kobayashi

    (Northwestern University)

  • Baozhen Zhang

    (Northwestern University
    Peking University Cancer Hospital and Institute)

  • Ziyu Zhao

    (Northwestern University)

  • Ye Hou

    (Northwestern University)

  • Xiaotao Wang

    (Northwestern University)

  • Yu Luan

    (Northwestern University)

  • Bei Jia

    (Penn State University)

  • Lena Stasiak

    (Northwestern University)

  • Josiah Hiu-yuen Wong

    (Northwestern University)

  • Qixuan Wang

    (Northwestern University)

  • Qi Jin

    (Northwestern University)

  • Qiushi Jin

    (Northwestern University)

  • Yihao Fu

    (Northwestern University)

  • Hongbo Yang

    (Northwestern University)

  • Ross C. Hardison

    (Penn State University)

  • Sinisa Dovat

    (Penn State University)

  • Leonidas C. Platanias

    (Northwestern University
    Jesse Brown Veterans Affairs Medical Center)

  • Yarui Diao

    (Duke University School of Medicine)

  • Yue Yang

    (Northwestern University)

  • Tomoko Yamada

    (Northwestern University)

  • Aaron D. Viny

    (Columbia University Irving Medical Center)

  • Ross L. Levine

    (Memorial Sloan Kettering Cancer Center)

  • David Claxton

    (Penn State University)

  • James. R. Broach

    (Penn State University)

  • Hong Zheng

    (Penn State University)

  • Feng Yue

    (Northwestern University
    Northwestern University)

Abstract

Acute myeloid leukaemia (AML) represents a set of heterogeneous myeloid malignancies, and hallmarks include mutations in epigenetic modifiers, transcription factors and kinases1–5. The extent to which mutations in AML drive alterations in chromatin 3D structure and contribute to myeloid transformation is unclear. Here we use Hi-C and whole-genome sequencing to analyse 25 samples from patients with AML and 7 samples from healthy donors. Recurrent and subtype-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing, ATAC with sequencing and CUT&Tag for CTCF, H3K27ac and H3K27me3 in the same AML samples also revealed extensive and recurrent AML-specific promoter–enhancer and promoter–silencer loops. We validated the role of repressive loops on their target genes by CRISPR deletion and interference. Structural variation-induced enhancer-hijacking and silencer-hijacking events were further identified in AML samples. Hijacked enhancers play a part in AML cell growth, as demonstrated by CRISPR screening, whereas hijacked silencers have a downregulating role, as evidenced by CRISPR-interference-mediated de-repression. Finally, whole-genome bisulfite sequencing of 20 AML and normal samples revealed the delicate relationship between DNA methylation, CTCF binding and 3D genome structure. Treatment of AML cells with a DNA hypomethylating agent and triple knockdown of DNMT1, DNMT3A and DNMT3B enabled the manipulation of DNA methylation to revert 3D genome organization and gene expression. Overall, this study provides a resource for leukaemia studies and highlights the role of repressive loops and hijacked cis elements in human diseases.

Suggested Citation

  • Jie Xu & Fan Song & Huijue Lyu & Mikoto Kobayashi & Baozhen Zhang & Ziyu Zhao & Ye Hou & Xiaotao Wang & Yu Luan & Bei Jia & Lena Stasiak & Josiah Hiu-yuen Wong & Qixuan Wang & Qi Jin & Qiushi Jin & Yi, 2022. "Subtype-specific 3D genome alteration in acute myeloid leukaemia," Nature, Nature, vol. 611(7935), pages 387-398, November.
  • Handle: RePEc:nat:nature:v:611:y:2022:i:7935:d:10.1038_s41586-022-05365-x
    DOI: 10.1038/s41586-022-05365-x
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    Citations

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    Cited by:

    1. Nicholas Sim & Jean-Michel Carter & Kamalakshi Deka & Benita Kiat Tee Tan & Yirong Sim & Suet-Mien Tan & Yinghui Li, 2024. "TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in triple-negative breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Hao Li & Zebei Han & Yu Sun & Fu Wang & Pengzhen Hu & Yuang Gao & Xuemei Bai & Shiyu Peng & Chao Ren & Xiang Xu & Zeyu Liu & Hebing Chen & Yang Yang & Xiaochen Bo, 2024. "CGMega: explainable graph neural network framework with attention mechanisms for cancer gene module dissection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Sophie G. Kellaway & Sandeep Potluri & Peter Keane & Helen J. Blair & Luke Ames & Alice Worker & Paulynn S. Chin & Anetta Ptasinska & Polina K. Derevyanko & Assunta Adamo & Daniel J. L. Coleman & Naee, 2024. "Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    4. Dunming Hua & Ming Gu & Xiao Zhang & Yanyi Du & Hangcheng Xie & Li Qi & Xiangjun Du & Zhidong Bai & Xiaopeng Zhu & Dechao Tian, 2024. "DiffDomain enables identification of structurally reorganized topologically associating domains," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Dominik Beck & Honghui Cao & Feng Tian & Yizhou Huang & Miao Jiang & Han Zhao & Xiaolu Tai & Wenqian Xu & Hansen J. Kosasih & David J. Kealy & Weiye Zhao & Samuel J. Taylor & Timothy A. Couttas & Gaox, 2024. "PU.1 eviction at lymphocyte-specific chromatin domains mediates glucocorticoid response in acute lymphoblastic leukemia," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    6. Sonali Narang & Yohana Ghebrechristos & Nikki A. Evensen & Nina Murrell & Sylwia Jasinski & Talia H. Ostrow & David T. Teachey & Elizabeth A. Raetz & Timothee Lionnet & Matthew Witkowski & Iannis Aifa, 2024. "Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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