Targeted attenuation of elevated histone marks at SNCA alleviates α‐synuclein in Parkinson's disease

• Published in: EMBO molecular medicine 2021-02, Vol.13 (2), p.e12188-n/a
• Main Authors: Guhathakurta, Subhrangshu, Kim, Jinil, Adams, Levi, Basu, Sambuddha, Song, Min Kyung, Adler, Evan, Je, Goun, Fiadeiro, Mariana Bernardo, Kim, Yoon‐Seong
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - genetics; Biopsy; Brain; CRISPR; CRISPR/Cas9; Dopamine receptors; Dopaminergic Neurons; EMBO09; EMBO27; Epigenetics; Gene expression; Histone Code; histone post‐translational modifications; Histones; Humans; Induced Pluripotent Stem Cells; Investigations; iPSCs; Movement disorders; Mutation; Neurodegenerative diseases; Parkinson Disease - genetics; Parkinson's disease; Proteins; Substantia nigra; Synuclein; Transcription; α‐synuclein
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202012188

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.