基脱甲酶KDM6A直接感知氧气以控制色素和细胞命运
Abhishek A Chakraborty1, Tuomas Laukka2, Matti Myllykoski2
1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Science (New York, N.Y.)
|March 16, 2019
概括
低氧直接影响通过氧敏感酶的基因组甲基化,独立于HIF或2-HG. 这种KDM6A的氧气感应机制调节细胞分化和染色质状态.
科学领域:
- 细胞生物学
- 表观遗传学
- 生物化学
背景情况:
- 氧气感应对甲状动物生命至关重要,
- 哺乳动物细胞利用依赖氧的酶,即依赖氧酸盐 (OG) 的二氧化酶 (2-OGDD),用于各种功能,包括组织蛋白脱甲基化.
- 缺氧影响基因组甲基化的确切机制,特别是HIF和2-HG的作用,尚不完全理解.
研究的目的:
- 调查缺氧是否直接影响基因组甲基酶.
- 为了确定缺氧诱导的组织蛋白甲基化是否依赖于缺氧诱导因子 (HIF) 或2-酸 (2-HG).
- 阐明特定的2-OGDD在氧气感应和细胞分化中的作用.
主要方法:
- 在低毒性条件下分析组织蛋白甲基化模式.
- 对KDM6A/UTX和KDM6B活动和氧气敏感性的评估.
- 研究KDM6A损失对细胞分化的影响.
- 在低氧细胞中恢复H3K27甲基化稳态的实验操作.
主要成果:
- 低氧促进了独立于HIF和2-HG的组胺甲基化.
- 鉴定出基因组脱甲基酶KDM6A/UTX与其对应基因组KDM6B不同,具有氧气敏感性.
- 通过抑制H3K27脱甲基和阻断细胞分化,KDM6A的损失模仿了缺氧.
- 在低氧细胞逆转分化缺陷中恢复H3K27甲基化平衡.
结论:
- 氧直接调节染色体调节剂,特别是KDM6A,以控制细胞命运.
- KDM6A作为直接的氧气传感器,将氧气水平与表观遗传修饰和细胞过程如分化联系起来.
- 这些发现揭示了一种新的氧气感应途径,涉及染色体修饰酶的直接表观遗传调节.
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