当前位置：科学网首页 > 小柯机器人 >详情
表观基因组的代谢调控驱动致死性小儿室管膜瘤
作者：小柯机器人 发布时间：2020/5/23 21:29:45

加拿大病童医院Michael D. Taylor、美国加州大学旧金山分校Jeremy N. Rich、匹兹堡大学Sameer Agnihotri等研究人员合作发现，表观基因组的代谢调控驱动致死性小儿室管膜瘤。这一研究成果于2020年5月22日在线发表在《细胞》上。

研究人员证明颅后窝A（PFA）室管膜瘤在低氧状态下得以维持，与特定代谢物的有限可用性相关，进而减少组蛋白甲基化，并增加组蛋白3第27位赖氨酸（H3K27）上的去甲基化和乙酰化。PFA室管膜瘤是在人类发育的前三个月中的细胞谱系中引发的，该谱系存在于受限的氧气中。与其他室管膜瘤不同，PFA细胞短暂暴露于环境氧会诱导不可逆的细胞毒性。
 
PFA肿瘤表现出低水平的H3K27me3基础水平，并且自相矛盾的是，抑制H3K27甲基化可特异性破坏PFA肿瘤的生长。靶向代谢和/或表观基因组为患有PFA室管膜瘤的婴儿提供了合理治疗的机会。
 
据悉，颅后窝A（PFA）室管膜瘤是婴幼儿的致命恶性肿瘤。缺乏高度复发的体细胞突变，PFA室管膜瘤被认为是表观遗传驱动的肿瘤，并且缺乏模型系统。
 
附：英文原文

Title: Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

Author: Kulandaimanuvel Antony Michealraj, Sachin A. Kumar, Leo J.Y. Kim, Florence M.G. Cavalli, David Przelicki, John B. Wojcik, Alberto Delaidelli, Andrea Bajic, Olivier Saulnier, Graham MacLeod, Ravi N. Vellanki, Maria C. Vladoiu, Paul Guilhamon, Winnie Ong, John J.Y. Lee, Yanqing Jiang, Borja L. Holgado, Alex Rasnitsyn, Ahmad A. Malik, Ricky Tsai, Cory M. Richman, Kyle Juraschka, Joonas Haapasalo, Evan Y. Wang, Pasqualino De Antonellis, Hiromichi Suzuki, Hamza Farooq, Polina Balin, Kaitlin Kharas, Randy Van Ommeren, Olga Sirbu, Avesta Rastan, Stacey L. Krumholtz, Michelle Ly, Moloud Ahmadi, Geneviève Deblois, Dilakshan Srikanthan, Betty Luu, James Loukides, Xiaochong Wu, Livia Garzia, Vijay Ramaswamy, Evgeny Kanshin, María Sánchez-Osuna, Ibrahim El-Hamamy, Fiona J. Coutinho, Panagiotis Prinos, Sheila Singh, Laura K. Donovan

Issue&Volume: 2020-05-22

Abstract: Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infantsand toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposedto be epigenetically driven tumors for which model systems are lacking. Here we demonstratethat PFA ependymomas are maintained under hypoxia, associated with restricted availabilityof specific metabolites to diminish histone methylation, and increase histone demethylationand acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a celllineage in the first trimester of human development that resides in restricted oxygen.Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen inducesirreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3,and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumorgrowth. Targeting metabolism and/or the epigenome presents a unique opportunity forrational therapy for infants with PFA ependymoma.

DOI: 10.1016/j.cell.2020.04.047

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30553-5

期刊信息
Cell：《细胞》，创刊于1974年。隶属于细胞出版社，最新IF：36.216
官方网址：https://www.cell.com/