Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms (RNA-Seq)

Epigenetic control of enhancers alters neuron functions and may be involved in Alzheimer’s disease (AD). Here, we identify enhancers in neurons contributing to AD by comprehensive fine-mapping of DNA methylation at enhancers, genome-wide. We examine 1.2 million CpG and CpH sites in enhancers in prefrontal cortex neurons of individuals with no/mild, moderate, and severe AD pathology (n=101). We identify 1,224 differentially methylated enhancer regions; most of which are hypomethylated at CpH sites in AD neurons. CpH methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.

增强子的表观遗传调控可改变神经元功能，并可能参与阿尔茨海默病（Alzheimer’s Disease, AD）的发病进程。本研究通过全基因组范围内对增强子区域DNA甲基化的精细化定位，筛选出与AD相关的神经元增强子。我们共纳入101名受试者，这些个体分别具有无/轻度、中度及重度AD病理特征，随后对其前额叶皮层神经元增强子区域内的120万个CpG位点（CpG）与CpH位点（CpH）进行了分析。本研究共鉴定出1224个差异甲基化增强子区域，其中绝大多数在AD神经元的CpH位点上呈现低甲基化状态。正常衰老的神经元中也会出现CpH甲基化丢失现象，但该过程在AD患者神经元中显著加速。表观组与转录组数据的整合分析显示，有丝分裂后AD神经元出现了促凋亡的细胞周期再激活现象。此外，AD神经元的DSCAML1基因内存在一个由大量显著低甲基化增强子构成的基因簇，该基因簇靶向调控BACE1基因。AD患者中这些增强子的低甲基化状态与BACE1转录本表达上调、淀粉样斑块与神经原纤维缠结沉积增加以及认知功能下降显著相关。