5-hydroxymethylcytosine-mediated epigenetic dynamics during neurodevelopment and aging [5hmC Capture and Seq]

DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base derived from 5-methylcytosine (5mC) accounts for ~40% of modified cytosine in brain, and has been implicated in DNA methylation-related plasticity. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We find developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC-regulated regions reveals stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by finding that its levels are inversely correlated with methyl-CpG-binding protein 2 (Mecp2) dosage, a protein encoded by a gene in which mutations cause Rett Syndrome. These data point toward critical roles for 5-hmC-mediated epigenetic modification in neurodevelopment and diseases. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. Profiling of 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by profiling 5-hmC in mouse cerebellum lacking MeCP2, a protein encoded by a gene in which mutations cause Rett Syndrome.

DNA甲基化（DNA methylation）的动态变化可影响大脑功能，且在神经疾病中发生异常改变。5-羟甲基胞嘧啶（5-hydroxymethylcytosine, 5-hmC）是一类由5-甲基胞嘧啶（5-methylcytosine, 5mC）衍生得到的DNA碱基，约占大脑中修饰胞嘧啶的40%，已被证实与DNA甲基化相关的神经可塑性密切相关。本研究在小鼠海马体（hippocampus）与小脑（cerebellum）的三个年龄阶段开展全基因组5-hmC图谱绘制，借此得以评估其在出生后神经发育至成年阶段的稳定性与动态调控规律。研究发现神经元细胞中存在发育程序性的5-hmC积累过程。对5-hmC调控区域的表观基因组定位分析显示，神经发育与衰老过程中存在稳定修饰及动态修饰的基因座。通过对人类小脑的5-hmC进行谱分析，本研究确立了5-hmC的保守基因组特征。上述研究结果表明，5-hmC介导的表观遗传修饰在神经发育与疾病发生中发挥关键作用。本研究再次在小鼠海马体与小脑的三个年龄阶段开展全基因组5-hmC图谱绘制，借此评估其在出生后神经发育至成年阶段的稳定性与动态调控规律。通过对人类小脑的5-hmC进行谱分析，我们确立了5-hmC的保守基因组特征。最后，我们通过对缺失MeCP2的小鼠小脑的5-hmC进行谱分析，证实5-hmC与神经发育性疾病相关——MeCP2是由一个其突变会导致雷特综合征（Rett Syndrome）的基因所编码的蛋白。