DNMT3A突变克隆的扩增与保守的表观遗传丧失相关
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DNMT3A突变克隆的扩增与保守的表观遗传丧失相关

浏览次数:    时间:2020-07-19

本期文章:《细胞—干细胞》:Online/在线发表

美国贝勒医学院Margaret A. Goodell、英国康桑格研究所Mathijs A. Sanders等研究人员合作发现,DNMT3A突变克隆的扩增与保守的表观遗传丧失相关。 该研究于2020年7月15日在线发表于《细胞—干细胞》。

据研究人员介绍,DNA甲基转移酶3A(DNMT3A)是克隆性造血(CH)中最常见的突变基因。DNMT3A体细胞突变发生在恶性肿瘤产生之前的造血干细胞(HSC)中,但是难以将其在恶性肿瘤之前的影响与野生型细胞进行比较,这不利于了解它们对转化的贡献。

 

为了解决这一限制,研究人员从生殖系镶嵌个体中产生了正常和DNMT3A突变型淋巴母细胞样细胞系,并且这些细胞共存了将近6年。突变细胞控制着血液系统,但不影响其他组织。深度测序揭示了正常克隆和突变克隆中相似的突变负担和特征,而表观遗传学分析揭示了突变克隆中致癌调节区DNA甲基化的局部丧失。这些区域与HSC和白血病样本中DNMT3A敲除引起的DNMT3A缺失敏感区域重叠。

 

这些结果表明,DNMT3A保持了保守的DNA甲基化模式,其丧失为造血细胞提供了明显的竞争优势。

 

附:英文原文

Title: Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual Is Associated with Conserved Epigenetic Erosion

Author: Ayala Tovy, Jaime M. Reyes, Michael C. Gundry, Lorenzo Brunetti, Henry Lee-Six, Mia Petljak, Hyun Jung Park, Anna G. Guzman, Carina Rosas, Aaron R. Jeffries, Emma Baple, Jonathan Mill, Andrew H. Crosby, Valerie Sency, Baozhong Xin, Heather E. Machado, Danielle Castillo, Jeffrey N. Weitzel, Wei Li, Michael R. Stratton, Peter J. Campbell, Heng Wang, Mathijs A. Sanders, Margaret A. Goodell

Issue&Volume: 2020-07-15

Abstract: DNA methyltransferase 3A (DNMT3A) is the most commonly mutated gene in clonal hematopoiesis(CH). Somatic DNMT3A mutations arise in hematopoietic stem cells (HSCs) many yearsbefore malignancies develop, but difficulties in comparing their impact before malignancywith wild-type cells have limited the understanding of their contributions to transformation.To circumvent this limitation, we derived normal and DNMT3A mutant lymphoblastoidcell lines from a germline mosaic individual in whom these cells co-existed for nearly6 decades. Mutant cells dominated the blood system, but not other tissues. Deep sequencingrevealed similar mutational burdens and signatures in normal and mutant clones, whileepigenetic profiling uncovered the focal erosion of DNA methylation at oncogenic regulatoryregions in mutant clones. These regions overlapped with those sensitive to DNMT3Aloss after DNMT3A ablation in HSCs and in leukemia samples. These results suggestthat DNMT3A maintains a conserved DNA methylation pattern, the erosion of which providesa distinct competitive advantage to hematopoietic cells.

DOI: 10.1016/j.stem.2020.06.018

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30285-X

期刊信息

Cell Stem Cell:《细胞—干细胞》,创刊于2007年。隶属于细胞出版社,最新IF:21.464
官方网址:https://www.cell.com/cell-stem-cell/home
投稿链接:https://www.editorialmanager.com/cell-stem-cell/default.aspx

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