Tlx3 promotes glutamatergic neuronal subtype specification through direct interactions with the chromatin modifier CBP.
Tlx3 promotes glutamatergic neuronal subtype specification through direct interactions with the chromatin modifier CBP.
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DOI：
10.1371/journal.pone.0135060
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hashino E
中科院分区：
文献类型：
--
作者：
Shimomura A;Patel D;Wilson SM;Koehler KR;Khanna R;Hashino E
神经系统的发育依赖于产生精确数量的兴奋性和抑制性神经元。同源结构域转录因子T细胞白血病3（Tlx 3）通过连续性地促进谷氨酸能兴奋性神经元的特化和抑制γ-氨基丁酸（GABA能）神经元的特化而作为主神经元命运调节剂发挥功能。然而，Tlx 3如何促进神经元亚型的特化知之甚少。在这项研究中，我们发现Tlx 3直接与表观遗传辅激活剂环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）结合蛋白（CBP）相互作用，Tlx 3同源结构域是这种相互作用所必需的。Tlx 3和CBP之间的相互作用被三个氨基酸环延伸（TALE）类同源结构域转录因子，前B细胞白血病转录因子3（Pbx 3）增强。使用小鼠胚胎干（ES）细胞稳定表达Tlx 3，我们发现Tlx 3和CBP之间的相互作用变得可检测只有在这些Tlx 3表达ES细胞致力于神经谱系，这与从ES细胞神经分化过程中Pbx 3表达增加相吻合。在经历神经分化的ES细胞中，缺乏同源结构域的突变Tlx 3的强制表达导致神经元亚型标记物的表达显著降低，但对泛神经标记物的表达几乎没有影响。总的来说，我们的研究结果强烈表明，Tlx 3和CBP之间的功能相互作用在神经元亚型规范中起着至关重要的作用，提供了新的见解的表观遗传调控机制，调节一组选择性的神经元亚型特异性基因在分化过程中的转录功效。
Nervous system development relies on the generation of precise numbers of excitatory and inhibitory neurons. The homeodomain transcription factor, T-cell leukemia 3 (Tlx3), functions as the master neuronal fate regulator by instructively promoting the specification of glutamatergic excitatory neurons and suppressing the specification of gamma-aminobutyric acid (GABAergic) neurons. However, how Tlx3 promotes glutamatergic neuronal subtype specification is poorly understood. In this study, we found that Tlx3 directly interacts with the epigenetic co-activator cyclic adenosine monophosphate (cAMP)-response element-binding protein (CREB)-binding protein (CBP) and that the Tlx3 homeodomain is essential for this interaction. The interaction between Tlx3 and CBP was enhanced by the three amino acid loop extension (TALE)-class homeodomain transcription factor, pre-B-cell leukemia transcription factor 3 (Pbx3). Using mouse embryonic stem (ES) cells stably expressing Tlx3, we found that the interaction between Tlx3 and CBP became detectable only after these Tlx3-expressing ES cells were committed to a neural lineage, which coincided with increased Pbx3 expression during neural differentiation from ES cells. Forced expression of mutated Tlx3 lacking the homeodomain in ES cells undergoing neural differentiation resulted in significantly reduced expression of glutamatergic neuronal subtype markers, but had little effect on the expression on pan neural markers. Collectively, our results strongly suggest that functional interplay between Tlx3 and CBP plays a critical role in neuronal subtype specification, providing novel insights into the epigenetic regulatory mechanism that modulates the transcriptional efficacy of a selective set of neuronal subtype-specific genes during differentiation.
影响因子：
2.1
作者：
Ju W;Wu J;Pritz MB;Khanna R
通讯作者：
Khanna R