Torres Rodrigo F, Hidalgo Cecilia, Kerr Bredford
Laboratory of Biology, Centro de Estudios CientíficosValdivia, Chile.
Biomedical Neuroscience Institute, Centro de Estudios Moleculares de la Célula, Department of Neuroscience and Physiology and Biophysics Program, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de ChileSantiago, Chile.
Front Mol Neurosci. 2017 Jun 13;10:188. doi: 10.3389/fnmol.2017.00188. eCollection 2017.
Mecp2 is a DNA methylation reader that plays a critical role in experience-dependent plasticity. Increasing evidence supports a role for epigenetic modifications in activity-induced gene expression. Hence, candidate genes related to such phenomena are of great interest. Ryanodine receptors are intracellular calcium channels that contribute to hippocampal synaptic plasticity, dendritic spine remodeling, and participate in learning and memory processes. Here we exposed mice to the enriched environment (EE) paradigm, which through increased stimulation induces experience dependent-plasticity, to explore a role for methyl-cytosines, and Mecp2 in directing Ryanodine receptor 3 () transcriptional activity. EE induced a hippocampal-specific increase in the methylation of discrete cytosines located at a isoform promoter; chromatin immunoprecipitation experiments revealed that EE increased Mecp2 binding to this isoform promoter. Interestingly, the experimental paradigm induced robust upregulation, accompanied by -dependent suppression of , a pathway driving synaptogenesis. In contrast to WT mice, mice showed diminished levels of and displayed impaired EE-induced upregulation, compromising dependent suppression of and experience-dependent structural plasticity. Based on these results, we propose that Mecp2 acts as a transcriptional activator of , contributing to experience-dependent plasticity.
Mecp2是一种DNA甲基化阅读器，在经验依赖的可塑性中发挥关键作用。越来越多的证据支持表观遗传修饰在活动诱导的基因表达中的作用。因此，与这种现象相关的候选基因备受关注。兰尼碱受体是细胞内钙通道，有助于海马突触可塑性、树突棘重塑，并参与学习和记忆过程。在这里，我们将小鼠置于丰富环境（EE）范式中，该范式通过增加刺激诱导经验依赖性可塑性，以探索甲基胞嘧啶和Mecp2在指导兰尼碱受体3（）转录活性中的作用。EE诱导位于异构体启动子处的离散胞嘧啶甲基化在海马中特异性增加；染色质免疫沉淀实验表明，EE增加了Mecp2与该异构体启动子的结合。有趣的是，实验范式诱导了强大的上调，同时伴随着对驱动突触形成的途径的依赖性抑制。与野生型小鼠相比，小鼠的水平降低，并且EE诱导的上调受损，损害了对的依赖性抑制和经验依赖性结构可塑性。基于这些结果，我们提出Mecp2作为的转录激活剂，有助于经验依赖性可塑性。
