Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Nat Commun. 2021 Jan 11;12(1):256. doi: 10.1038/s41467-020-20511-7.
In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltransferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 regulates the development of growth hormone-releasing hormone (GHRH)-producing neurons in the mouse hypothalamus. Our two Mll4 mutant mouse models exhibit dwarfism phenotype and impairment of the developmental programs for GHRH-neurons. Our ChIP-seq analysis reveals that, in the developing mouse hypothalamus, Mll4 interacts with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 results in a marked reduction of histone marks of active transcription, while treatment with the histone deacetylase inhibitor AR-42 rescues the histone mark signature and restores GHRH-neuronal production in Mll4 mutant mice. Our results suggest that the developmental dysregulation of Mll4-directed epigenetic control of transcription plays a role in the development of GHRH-neurons and dwarfism phenotype in mice.
在人类中，编码组蛋白 H3-赖氨酸 4-甲基转移酶的 MLL4 失活突变导致歌舞伎综合征（KS）。虽然矮小症是 KS 的一个主要特征，但潜在的病因仍不清楚。在这里，我们报告 Mll4 调节生长激素释放激素（GHRH）产生神经元在小鼠下丘脑的发育。我们的两种 Mll4 突变小鼠模型表现出矮小症表型和 GHRH-神经元发育程序受损。我们的 ChIP-seq 分析表明，在发育中的小鼠下丘脑，Mll4 与转录因子 Nrf1 相互作用，触发 GHRH-神经元基因的表达。有趣的是，Mll4 的缺失导致活跃转录的组蛋白标记明显减少，而组蛋白去乙酰化酶抑制剂 AR-42 的处理可挽救 Mll4 突变小鼠中的组蛋白标记特征，并恢复 GHRH-神经元的产生。我们的研究结果表明，Mll4 指导的转录表观遗传调控的发育失调在小鼠的 GHRH-神经元发育和矮小症表型中起作用。
