Developmental and Stem Cell Biology Program, Hospital for Sick Children, 555 University Ave., Toronto, ON, Canada.
Dev Cell. 2010 Jan 19;18(1):114-25. doi: 10.1016/j.devcel.2009.10.023.
Increasing evidence indicates that epigenetic changes regulate cell genesis. Here, we ask about neural precursors, focusing on CREB binding protein (CBP), a histone acetyltransferase that, when haploinsufficient, causes Rubinstein-Taybi syndrome (RTS), a genetic disorder with cognitive dysfunction. We show that neonatal cbp(+/-) mice are behaviorally impaired, displaying perturbed vocalization behavior. cbp haploinsufficiency or genetic knockdown with siRNAs inhibited differentiation of embryonic cortical precursors into all three neural lineages, coincident with decreased CBP binding and histone acetylation at promoters of neuronal and glial genes. Inhibition of histone deacetylation rescued these deficits. Moreover, CBP phosphorylation by atypical protein kinase C zeta was necessary for histone acetylation at neural gene promoters and appropriate differentiation. These data support a model in which environmental cues regulate CBP activity and histone acetylation to control neural precursor competency to differentiate, and indicate that cbp haploinsufficiency disrupts this mechanism, thereby likely causing cognitive dysfunction in RTS.
越来越多的证据表明，表观遗传变化调节细胞发生。在这里，我们关注神经前体细胞，特别关注 CREB 结合蛋白（CBP），它是一种组蛋白乙酰转移酶，当单倍不足时会导致 Rubinstein-Taybi 综合征（RTS），这是一种具有认知功能障碍的遗传疾病。我们发现新生的 cbp(+/-) 小鼠在行为上受损，表现出发声行为紊乱。cbp 单倍不足或用 siRNA 进行基因敲低会抑制胚胎皮质前体细胞向所有三种神经谱系的分化，同时伴随着神经元和神经胶质基因启动子处 CBP 结合和组蛋白乙酰化的减少。组蛋白去乙酰化抑制剂可挽救这些缺陷。此外，非典型蛋白激酶 C zeta 对 CBP 的磷酸化对于神经基因启动子处的组蛋白乙酰化和适当的分化是必需的。这些数据支持了这样一种模型，即环境线索调节 CBP 活性和组蛋白乙酰化，以控制神经前体细胞分化的能力，并表明 cbp 单倍不足破坏了这种机制，从而可能导致 RTS 中的认知功能障碍。
