通过表观遗传激活MYC表达,L-2-氧氨酸会损害神经元的分化
Wen Gu1, Xun Wang1,2, Ashley Solmonson1
1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
bioRxiv : the preprint server for biology
|July 16, 2025
概括
由于L2HGDH缺陷而产生的L-2-基酸盐积累,通过激活MYC瘤基因,驱动自我更新并抑制神经元发育,损害神经干细胞分化.
科学领域:
- 生物化学 生物化学
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
背景情况:
- 高水平的L-和D-2-基酸盐 (L-2HG,D-2HG) 与神经发育障碍和癌症有关.
- L-2HG和D-2HG通过调节参与脱甲基化的αKG依赖型二氧化酶,影响表观遗传学.
- 缺乏L-2HG脱酶 (L2HGDH) 会导致L-2HG的积累,导致神经障碍和癌症风险.
研究的目的:
- 通过诱导多能干细胞 (iPSC) 模型,研究L2HGDH缺乏对神经原生细胞 (NPC) 功能和神经元分化的影响.
- 阐明L2HGDH缺乏的神经学和瘤学方面的分子机制.
主要方法:
- 利用一种同源的,来自患者的iPSC系统来建模L2HGDH缺乏症.
- 在2D培养和皮层球形体中分析了NPC增殖,克隆性和神经元分化.
- 研究了表观遗传修饰,特别是基因组甲基化 (H3K4me2,H3K4me3) 和基因表达 (MYC).
- 使用基因编辑和药理抑制来评估L-2HG和MYC的影响.
主要成果:
- 缺乏L2HGDH导致L-2HG的积累,NPC的过度扩散,克隆性增加和神经元差异化缺陷.
- L-2HG积累抑制了KDM5基因组脱甲基酶,导致H3K4me2和H3K4me3.3的广泛保留.
- 在MYC位点观察到H3K4me2/H3K4me3标志升高,导致MYC表达高.
- 将MYC表达在遗传或药理上正常化完全逆转了缺陷的神经元分化.
结论:
- 在iPSC中L2HGDH缺乏会激活MYC瘤基因,促进干细胞自我更新和抑制神经元谱系的承诺.
- 在L2HGDH缺乏的主要代谢干扰驱动瘤基因激活和发育缺陷.
- 准MYC为与L2HGDH缺乏相关的神经疾病提供了潜在的治疗策略.
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