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科学家揭示急性骨髓性白血病的亚型特异性三维基因组改变
作者:小柯机器人 发布时间:2022/10/30 19:47:39

近日,美国西北大学教授岳峰等研究人员合作揭示急性骨髓性白血病的亚型特异性三维基因组改变。相关论文于2022年10月26日在线发表在《自然》杂志上。

研究人员使用Hi-C和全基因组测序来分析了25个急性骨髓性白血病(AML)患者的样本和7个健康捐赠者的样本。在A/B区、拓扑关联域和染色质环中发现了反复出现的和亚型特异性的改变。在相同的AML样本中,RNA测序、ATAC测序和CTCF、H3K27ac和H3K27me3的CUT&Tag也显示了广泛和反复出现的AML特异性启动子-增强子和启动子-沉默子环。研究人员通过CRISPR删除和干扰验证了抑制性环对其靶基因的作用。结构变异引起的增强子劫持和沉默者劫持事件在AML样本中被进一步确定。正如CRISPR筛选所证明的,被劫持的增强子在AML细胞生长中起作用,而被劫持的沉默子则具有下调作用,这一点在CRISPR干扰介导的去抑制中得到证明。

最后,20个AML和正常样本的全基因组亚硫酸氢盐测序显示了DNA甲基化、CTCF结合和三维基因组结构之间的微妙关系。用DNA低甲基化剂处理AML细胞,并对DNMT1、DNMT3A和DNMT3B进行三重敲除,能够操纵DNA甲基化来恢复3D基因组组织和基因表达。总的来说,这项研究为白血病研究提供了一个资源,并强调了抑制性环和劫持的顺式元件在人类疾病中的作用。

据介绍,AML代表了一组异质性骨髓性恶性肿瘤,其特征包括表观遗传修饰因子、转录因子和激酶的突变。目前还不清楚AML中的突变在多大程度上驱动了染色质三维结构的改变并促成了骨髓的转化。

附:英文原文

Title: Subtype-specific 3D genome alteration in acute myeloid leukaemia

Author: Xu, Jie, Song, Fan, Lyu, Huijue, Kobayashi, Mikoto, Zhang, Baozhen, Zhao, Ziyu, Hou, Ye, Wang, Xiaotao, Luan, Yu, Jia, Bei, Stasiak, Lena, Wong, Josiah Hiu-yuen, Wang, Qixuan, Jin, Qi, Jin, Qiushi, Fu, Yihao, Yang, Hongbo, Hardison, Ross C., Dovat, Sinisa, Platanias, Leonidas C., Diao, Yarui, Yang, Yue, Yamada, Tomoko, Viny, Aaron D., Levine, Ross L., Claxton, David, Broach, James. R., Zheng, Hong, Yue, Feng

Issue&Volume: 2022-10-26

Abstract: Acute myeloid leukaemia (AML) represents a set of heterogeneous myeloid malignancies, and hallmarks include mutations in epigenetic modifiers, transcription factors and kinases1,2,3,4,5. 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.

DOI: 10.1038/s41586-022-05365-x

Source: https://www.nature.com/articles/s41586-022-05365-x

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html