Targeted attenuation of elevated histone marks at SNCA alleviates α-synuclein in Parkinson's disease.
Targeted attenuation of elevated histone marks at SNCA alleviates α-synuclein in Parkinson's disease.
复制标题
靶向减弱SNCA升高的组蛋白标记物使帕金森病患者的α-突触核蛋白消失
DOI：
10.15252/emmm.202012188
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发表时间：
2021-02-05
影响因子：
11.1
通讯作者：
Kim YS
中科院分区：
文献类型：
--
作者：
Guhathakurta S;Kim J;Adams L;Basu S;Song MK;Adler E;Je G;Fiadeiro MB;Kim YS
α-突触核蛋白的表观遗传失调在帕金森病（PD）中起着关键作用。使用ENCODE数据库对SNCA启动子进行分析，发现存在重要的组蛋白翻译后修饰（PTM），包括转录促进标记H3 K4 me 3和H3 K27 ac，以及抑制标记H3 K27 me 3。我们研究了对照组和PD患者死后大脑中的这些组蛋白标记，并观察到在穿刺活检和NeuN阳性神经元细胞核样本中，PD患者黑质（SN）的SNCA启动子处仅H3 K4 me 3显著升高。为了了解H3 K4 me 3在α-突触核蛋白调控中的重要性，我们开发了基于CRISPR/dCas 9的基因座特异性H3 K4 me 3去甲基化系统，其中JARID 1A的催化结构域被募集到SNCA启动子。这种CRISPR/dCas 9 SunTag-JARID 1A显著减少SNCA启动子处的H3 K4 me 3，并伴随减少神经元细胞系SH-SY 5 Y和特发性PD-iPSC衍生的多巴胺能神经元中的α-突触核蛋白。总之，这项研究表明，PD中的α-突触核蛋白表达受SNCA的组蛋白PTM控制，SNCA的组蛋白景观的调节可以降低α-突触核蛋白表达。组蛋白翻译后修饰在帕金森病（PD）中α-突触核蛋白表达的调节中起主要作用。SNCA启动子处H3 K4 me 3的基因座特异性编辑恢复了PD背景下神经元中α-突触核蛋白的失调表达。
Epigenetic deregulation of α‐synuclein plays a key role in Parkinson’s disease (PD). Analysis of the SNCA promoter using the ENCODE database revealed the presence of important histone post‐translational modifications (PTMs) including transcription‐promoting marks, H3K4me3 and H3K27ac, and repressive mark, H3K27me3. We investigated these histone marks in post‐mortem brains of controls and PD patients and observed that only H3K4me3 was significantly elevated at the SNCA promoter of the substantia nigra (SN) of PD patients both in punch biopsy and in NeuN‐positive neuronal nuclei samples. To understand the importance of H3K4me3 in regulation of α‐synuclein, we developed CRISPR/dCas9‐based locus‐specific H3K4me3 demethylating system where the catalytic domain of JARID1A was recruited to the SNCA promoter. This CRISPR/dCas9 SunTag‐JARID1A significantly reduced H3K4me3 at SNCA promoter and concomitantly decreased α‐synuclein both in the neuronal cell line SH‐SY5Y and idiopathic PD‐iPSC derived dopaminergic neurons. In sum, this study indicates that α‐synuclein expression in PD is controlled by SNCA’s histone PTMs and modulation of the histone landscape of SNCA can reduce α‐synuclein expression. Histone posttranslational modifications play a major role in the regulation of α‐synuclein expression in Parkinson’s disease (PD). Locus‐specific editing of H3K4me3 at the SNCA promoter reverts the deregulated expression of α‐synuclein in neurons in the context of PD.