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

Autor: Guhathakurta S; Burnett School of Biomedical Sciences, UCF College of Medicine, University of Central Florida, Orlando, FL, USA., Kim J; Burnett School of Biomedical Sciences, UCF College of Medicine, University of Central Florida, Orlando, FL, USA.; Nexmos, Yongin-Si, South Korea., Adams L; Burnett School of Biomedical Sciences, UCF College of Medicine, University of Central Florida, Orlando, FL, USA.; Robert Wood Johnson Medical School Institute for Neurological Therapeutics, Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA., Basu S; Burnett School of Biomedical Sciences, UCF College of Medicine, University of Central Florida, Orlando, FL, USA., Song MK; Burnett School of Biomedical Sciences, UCF College of Medicine, University of Central Florida, Orlando, FL, USA.; Robert Wood Johnson Medical School Institute for Neurological Therapeutics, Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA., Adler E; Burnett School of Biomedical Sciences, UCF College of Medicine, University of Central Florida, Orlando, FL, USA., Je G; Burnett School of Biomedical Sciences, UCF College of Medicine, University of Central Florida, Orlando, FL, USA., Fiadeiro MB; Burnett School of Biomedical Sciences, UCF College of Medicine, University of Central Florida, Orlando, FL, USA., Kim YS; Burnett School of Biomedical Sciences, UCF College of Medicine, University of Central Florida, Orlando, FL, USA.; Robert Wood Johnson Medical School Institute for Neurological Therapeutics, Rutgers Biomedical and Health Sciences, Piscataway, NJ, USA.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2021 Feb 05; Vol. 13 (2), pp. e12188. Date of Electronic Publication: 2021 Jan 11.
DOI: 10.15252/emmm.202012188
Abstrakt: 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.
(© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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