Subtype-specific 3D genome alteration in acute myeloid leukaemia

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, Yihao Fu, Hongbo Yang, Ross C. Hardison, Sinisa Dovat, Leonidas C. PlataniasYarui Diao, Yue Yang, Tomoko Yamada, Aaron D. Viny, Ross L. Levine, David Claxton, James R. Broach, Hong Zheng, Feng Yue

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)387-398
Number of pages12
JournalNature
Volume611
Issue number7935
DOIs
StatePublished - Nov 10 2022

All Science Journal Classification (ASJC) codes

  • General

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