BACKGROUND Hexanucleotide repeat expansions of the G4C2 motif in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Tissues from C9ALS/FTD patients and from mouse models of ALS show RNA foci, dipeptide-repeat proteins, and notably, widespread alterations in the transcriptome. Epigenetic processes regulate gene expression without changing DNA sequences and therefore could account for the altered transcriptome profiles in C9ALS/FTD; here, we explore whether the critical repressive marks H3K9me2 and H3K9me3 are altered in a recently developed C9ALS/FTD BAC mouse model (C9BAC). RESULTS Chromocenters that constitute pericentric constitutive heterochromatin were visualized as DAPI- or Nucblue-dense foci in nuclei. Cultured C9BAC astrocytes exhibited a reduced staining signal for H3K9me3 (but not for H3K9me2) at chromocenters that was accompanied by a marked decline in the global nuclear level of this mark. Similar depletion of H3K9me3 at chromocenters was detected in astrocytes and neurons of the spinal cord, motor cortex, and hippocampus of C9BAC mice. The alterations of H3K9me3 in the hippocampus of C9BAC mice led us to identify previously undetected neuronal loss in CA1, CA3, and dentate gyrus, as well as hippocampal-dependent cognitive deficits. CONCLUSIONS Our data indicate that a loss of the repressive mark H3K9me3 in astrocytes and neurons in the central nervous system of C9BAC mice represents a signature during neurodegeneration and memory deficit of C9ALS/FTD.

中文翻译：

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在C9orf72 BAC转基因小鼠中，星形胶质细胞和神经元中沉默表观遗传标记H3K9me3的广泛丧失以及海马依赖性认知障碍。

背景技术在C9ORF72基因的非编码区中G4C2基序的六核苷酸重复扩增是肌萎缩性侧索硬化症（ALS）和额颞痴呆（FTD）的最常见遗传原因。C9ALS / FTD患者和ALS小鼠模型的组织显示RNA病灶，二肽重复蛋白，尤其是转录组中的广泛变化。表观遗传过程调节基因表达而不改变DNA序列，因此可以解释C9ALS / FTD中转录组谱的改变。在这里，我们探讨在最近开发的C9ALS / FTD BAC小鼠模型（C9BAC）中，关键的抑制标记H3K9me2和H3K9me3是否发生了改变。结果构成中心周围组成型染色质的色心被可视化为DAPI或Nucblue密集的细胞核。培养的C9BAC星形胶质细胞在色中心显示出对H3K9me3的染色信号减少（但对H3K9me2没有），同时伴随着该标记的整体核水平显着下降。在C9BAC小鼠的星形胶质细胞和脊髓，运动皮层和海马的神经元中，在发色中心检测到类似的H3K9me3消耗。C9BAC小鼠海马中H3K9me3的变化使我们能够鉴定出先前未检测到的CA1，CA3和齿状回的神经元丢失，以及海马依赖性认知缺陷。结论我们的数据表明，C9BAC小鼠中枢神经系统星形胶质细胞和神经元中阻遏标记H3K9me3的缺失代表了C9ALS / FTD神经退行性变和记忆缺陷期间的特征。