Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice
Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice
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DOI：
10.1186/s13148-020-0816-9
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发表时间：
2020-02-18
影响因子：
5.7
通讯作者：
van Zundert, Brigitte
中科院分区：
文献类型：
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作者：
Jury, Nur;Abarzua, Sebastian;van Zundert, Brigitte
C9ORF72基因非编码区G(4)C(2)基序的六核苷酸重复扩增是肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因。来自C9ALS/FTD患者和ALS小鼠模型的组织显示出RNA灶，二肽重复蛋白，特别是转录组的广泛改变。表观遗传过程在不改变DNA序列的情况下调节基因表达，因此可以解释C9ALS/FTD中转录组谱的改变；在这里，我们探讨了关键抑制标记H3K9me2和H3K9me3是否在最近开发的C9ALS/FTD BAC小鼠模型（C9BAC）中发生改变。结果构成中心周围组成异染色质的色中心在细胞核中表现为DAPI-或核蓝密集灶。培养的C9BAC星形胶质细胞在色中心显示H3K9me3染色信号降低（但H3K9me2没有），并伴有该标记的整体核水平明显下降。在C9BAC小鼠的脊髓、运动皮层和海马的星形胶质细胞和神经元中也检测到类似的H3K9me3在色中心的缺失。C9BAC小鼠海马中H3K9me3的改变使我们确定了CA1、CA3和齿状回中先前未被发现的神经元丢失，以及海马依赖性认知缺陷。结论C9BAC小鼠中枢神经系统星形细胞和神经元中抑制标记H3K9me3的缺失是C9ALS/FTD神经变性和记忆缺陷的一个特征。
Background Hexanucleotide repeat expansions of the G(4)C(2) 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.