TY - JOUR
T1 - Subtype-specific 3D genome alteration in acute myeloid leukaemia
AU - Xu, Jie
AU - Song, Fan
AU - Lyu, Huijue
AU - Kobayashi, Mikoto
AU - Zhang, Baozhen
AU - Zhao, Ziyu
AU - Hou, Ye
AU - Wang, Xiaotao
AU - Luan, Yu
AU - Jia, Bei
AU - Stasiak, Lena
AU - Wong, Josiah Hiu yuen
AU - Wang, Qixuan
AU - Jin, Qi
AU - Jin, Qiushi
AU - Fu, Yihao
AU - Yang, Hongbo
AU - Hardison, Ross C.
AU - Dovat, Sinisa
AU - Platanias, Leonidas C.
AU - Diao, Yarui
AU - Yang, Yue
AU - Yamada, Tomoko
AU - Viny, Aaron D.
AU - Levine, Ross L.
AU - Claxton, David
AU - Broach, James R.
AU - Zheng, Hong
AU - Yue, Feng
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/11/10
Y1 - 2022/11/10
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-022-05365-x
DO - 10.1038/s41586-022-05365-x
M3 - Article
C2 - 36289338
AN - SCOPUS:85140627544
SN - 0028-0836
VL - 611
SP - 387
EP - 398
JO - Nature
JF - Nature
IS - 7935
ER -