Genome Center and Medical Microbiology and Immunology, School of Medicine, University of California, Davis, California 95616, USA.
J Cell Biochem. 2011 Feb;112(2):365-73. doi: 10.1002/jcb.22958.
Epigenetic mechanisms play essential roles in mammalian neurodevelopment and genetic mutations or chromosomal deletions or duplications of epigenetically regulated loci or pathways result in several important human neurodevelopmental disorders. Postnatal mammalian neurons have among the most structured and dynamic nuclear organization of any cell type. Human chromosome 15q11-13 is an imprinted locus required for normal neurodevelopment and is regulated by a plethora of epigenetic mechanisms in neurons, including multiple noncoding RNAs, parentally imprinted transcription and histone modifications, large-scale chromatin decondensation, and homologous pairing in mature neurons of the mammalian brain. Here, we describe the multiple epigenetic layers regulating 15q11-13 gene expression and chromatin dynamics in neurons and propose a model of how noncoding RNAs may influence the unusual neuronal chromatin structure and dynamics at this locus. We also discuss the need for improved neuronal cell culture systems that model human 15q11-13 and other neurodevelopmental disorders with epigenetic bases in order to test the mechanisms of chromatin dynamics and nuclear organization in neurons. Induced pluripotent stem cells and other stem cell technologies hold promise for improved understanding of and therapeutic interventions for multiple human neurodevelopmental disorders.
表观遗传机制在哺乳动物神经发育中发挥着重要作用，表观遗传调控基因座或通路的基因突变或染色体缺失或重复导致了几种重要的人类神经发育障碍。出生后的哺乳动物神经元具有所有细胞类型中最具结构和动态的核组织。人类 15 号染色体 q11-13 是一个印迹基因座，是正常神经发育所必需的，受神经元中多种表观遗传机制的调控，包括多种非编码 RNA、亲本印迹转录和组蛋白修饰、大规模染色质解凝聚以及成熟哺乳动物大脑神经元中的同源配对。在这里，我们描述了调节神经元中 15q11-13 基因表达和染色质动力学的多个表观遗传层，并提出了一种模型，说明非编码 RNA 如何影响该基因座上的异常神经元染色质结构和动力学。我们还讨论了需要改进的神经元细胞培养系统，以模拟人类 15q11-13 和其他具有表观遗传基础的神经发育障碍，以便测试神经元中染色质动力学和核组织的机制。诱导多能干细胞和其他干细胞技术有望改善对多种人类神经发育障碍的理解和治疗干预。
