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 language | English (US) |
|---|---|
| Pages (from-to) | 387-398 |
| Number of pages | 12 |
| Journal | Nature |
| Volume | 611 |
| Issue number | 7935 |
| DOIs | |
| State | Published - Nov 10 2022 |
Funding
F.Y. is supported by NIH grants R35GM124820, 1R01HG009906, R01HG011207, U01CA200060 and R24DK106766 (R.C.H. and F.Y.). We acknowledge the use of the Integrated Genomics Operation Core, funded by the Memorial Sloan Kettering Cancer Center Support Grant NIH P30 CA008748. This work was supported by National Cancer Institute R35 CA197594-01A1 (R.L.L.), National Cancer Institute R01 CA216421 (R.L.L.) and National Cancer Institute PS-OC U54 CA143869-05 (R.L.L). A.D.V. is supported by National Cancer Institute career development grant K08 CA215317, the William Raveis Charitable Fund Fellowship of the Damon Runyon Cancer Research Foundation (DRG 117-15) and an Evans MDS Young Investigator grant from the Edward P. Evans Foundation. T.Y. is supported by U01DA053691. The CUT&Tag reagent pA–Tn5 was provided as a gift from S. Henikoff’s Lab at Fred Hutchinson Cancer Research Center. The dCas9-UTX plasmid was provided as a gift by S. M. Offer’s Lab at Mayo Clinic. F.Y. is supported by NIH grants R35GM124820, 1R01HG009906, R01HG011207, U01CA200060 and R24DK106766 (R.C.H. and F.Y.). We acknowledge the use of the Integrated Genomics Operation Core, funded by the Memorial Sloan Kettering Cancer Center Support Grant NIH P30 CA008748. This work was supported by National Cancer Institute R35 CA197594-01A1 (R.L.L.), National Cancer Institute R01 CA216421 (R.L.L.) and National Cancer Institute PS-OC U54 CA143869-05 (R.L.L). A.D.V. is supported by National Cancer Institute career development grant K08 CA215317, the William Raveis Charitable Fund Fellowship of the Damon Runyon Cancer Research Foundation (DRG 117-15) and an Evans MDS Young Investigator grant from the Edward P. Evans Foundation. T.Y. is supported by U01DA053691. The CUT&Tag reagent pA–Tn5 was provided as a gift from S. Henikoff’s Lab at Fred Hutchinson Cancer Research Center. The dCas9-UTX plasmid was provided as a gift by S. M. Offer’s Lab at Mayo Clinic.
ASJC Scopus subject areas
- General
