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Targeted attenuation of elevated histone marks at SNCA alleviates α‐synuclein in Parkinson's disease
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Targeted attenuation of elevated histone marks at SNCA alleviates α‐synuclein in Parkinson's disease
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Journal Article
Targeted attenuation of elevated histone marks at SNCA alleviates α‐synuclein in Parkinson's disease
2021
Overview
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.
Synopsis
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.
α‐synuclein expression is controlled by epigenetic regulation.
H3K4me3 is heavily enriched at the
SNCA
promoter in PD patient brains.
Locus‐specific editing of H3K4me3 reduces neuronal α‐synuclein expression in PD.
Graphical Abstract
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.
Publisher
Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
Subject
