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ZMYND11抑制KMT2A,使神经元发育程序成为可能

Alexander W Greben^1,2, Xiaoli S Wu¹, Josephine E Robb¹

¹Department of Neurobiology, Harvard Medical School, Boston, MA, USA.

bioRxiv : the preprint server for biology

|November 24, 2025

概括

ZMYND11中的突变会导致与ZMYND11相关的综合征性智力障碍 (ZRSID). 神经元中ZMYND11的丧失通过抑制KMT2A来破坏基因表达,这表明KMT2A抑制是潜在的ZRSID疗法.

科学领域:

神经科学是一个神经科学.
遗传学遗传学是一个
染色体生物学染色体生物学

背景情况:

ZMYND11突变导致ZMYND11相关综合征性智力障碍 (ZRSID),其特征是发育迟缓和发作.
在小鼠中,神经元ZMYND11损失导致异常基因表达,神经元连接性降低和行为缺陷.

研究的目的:

研究ZMYND11调节大脑中的基因表达的机制.
探索针对ZRSID的KMT2A的治疗潜力.

主要方法:

使用ZMYND11淘汰赛小鼠模型研究ZRSID.
研究了ZMYND11与基因素甲基转移酶KMT2A (MLL1) 的相互作用.
在初级皮层神经元中使用了被降解标记的ZMYND11小鼠模型和KMT2A抑制剂revumenib.

主要成果:

神经元中ZMYND11的删除会提高非神经元基因程序的调节,导致树突分支受损和运动异常.
ZMYND11直接抑制KMT2A,KMT2A是癌症和发育基因程序中的一个关键参与者.
与ZRSID相关的突变破坏了ZMYND11-KMT2A相互作用,突出显示了它在大脑发育中的重要性.
由ZMYND11损失引起的KMT2A抑制与revumenib减弱的基因表达变化.

结论:

ZMYND11通过抑制KMT2A.通过抑制神经元基因表达的关键调节剂.
ZMYND11-KMT2A相互作用对于正常的大脑发育至关重要.
针对KMT2A活动为ZRSID提供了潜在的治疗策略.

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