小柯机器人

英国剑桥大学Brian J. P. Huntly课题组的一项最新研究发现，白血病诱导过程中的突变协同重塑染色质可及性、组蛋白修饰和三维DNA拓扑结构来改变基因表达。相关论文于2021年9月23日在线发表在《自然—遗传学》杂志上。

研究人员将综合基因组学方法应用于小鼠等位基因系列，这模拟了急性髓性白血病（AML）中两个最常见的突变：Flt3-ITD和Npm1c。然后，研究人员解读了每个突变对表观遗传图谱和基因组组织改变的贡献，并推断出突变如何在诱导AML方面发挥协同作用。研究表明，Flt3-ITD向染色质发出信号来改变表观遗传环境，并与Npm1c的突变协同改变基因表达和驱动白血病诱导。

这些分析还能够识别长程顺式调控回路，包括以前未知的Hoxa基因座超级增强子，以及更大和更详细的基因调控网络，由包括PU.1和IRF8在内的转录因子驱动，并且通过扰乱网络成员证明了其重要性。

据介绍，转录改变是AML的一个主要特征。然而，突变究竟是如何协同重塑表观遗传图谱并重新连接三维DNA拓扑结构的，目前尚不清楚。

附：英文原文

Title: Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression

Author: Yun, Haiyang, Narayan, Nisha, Vohra, Shabana, Giotopoulos, George, Mupo, Annalisa, Madrigal, Pedro, Sasca, Daniel, Lara-Astiaso, David, Horton, Sarah J., Agrawal-Singh, Shuchi, Meduri, Eshwar, Basheer, Faisal, Marando, Ludovica, Gozdecka, Malgorzata, Dovey, Oliver M., Castillo-Venzor, Aracely, Wang, Xiaonan, Gallipoli, Paolo, Mller-Tidow, Carsten, Osborne, Cameron S., Vassiliou, George S., Huntly, Brian J. P.

Issue&Volume: 2021-09-23

Abstract: Altered transcription is a cardinal feature of acute myeloid leukemia (AML); however, exactly how mutations synergize to remodel the epigenetic landscape and rewire three-dimensional DNA topology is unknown. Here, we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML: Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. Our studies demonstrate that Flt3-ITD signals to chromatin to alter the epigenetic environment and synergizes with mutations in Npm1c to alter gene expression and drive leukemia induction. These analyses also allow the identification of long-range cis-regulatory circuits, including a previously unknown superenhancer of Hoxa locus, as well as larger and more detailed gene-regulatory networks, driven by transcription factors including PU.1 and IRF8, whose importance we demonstrate through perturbation of network members. Mice bearing mutations in Flt3-ITD and Npm1c, which are commonly found in acute myeloid leukemia, are used to characterize the cooperative effects of these cancer drivers on the cellular epigenome and three-dimensional genome conformation during tumor development.

DOI: 10.1038/s41588-021-00925-9

Source: https://www.nature.com/articles/s41588-021-00925-9

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