YY1 binds to α-synuclein 3′-flanking region SNP and stimulates antisense noncoding RNA expression

Abstract

α-synuclein (SNCA) is an established susceptibility gene for Parkinson's disease (PD), one of the most common human neurodegenerative disorders. Increased SNCA is considered to lead to PD and dementia with Lewy bodies. Four single-nucleotide polymorphisms (SNPs) in SNCA 3' region were prominently associated with PD among different ethnic groups. To examine how these SNPs influence disease susceptibility, we analyzed their potential effects on SNCA gene expression. We found that rs356219 showed allele-specific features. Gel shift assay using nuclear extracts from SH-SY5Y cells showed binding of one or more proteins to the protective allele, rs356219-A. We purified the rs356219-A-protein complex with DNA affinity beads and identified a bound protein using mass spectrometry. This protein, YY1 (Yin Yang 1), is an ubiquitous transcription factor with multiple functions. We next investigated SNCA expression change in SH-SY5Y cells by YY1 transfection. We also analyzed the expression of antisense noncoding RNA (ncRNA) RP11-115D19.1 in SNCA 3'-flanking region, because rs356219 is located in intron of RP11-115D19.1. Little change was observed in SNCA expression levels; however, RP11-115D19.1 expression was prominently stimulated by YY1. In autopsied cortices, positive correlation was observed among RP11-115D19.1, SNCA and YY1 expression levels, suggesting their functional interactions in vivo. Knockdown of RP11-115D19.1 increased SNCA expression significantly in SH-SY5Y cells, suggesting its repressive effect on SNCA expression. Our findings of the protective allele-specific YY1 and antisense ncRNA raised a novel possible mechanism to regulate SNCA expression.

Basic biology and therapeutic implications of lncRNA

“…For example, 17 of the 23 SNPs already implicated in type 1 diabetes were observed within a long non-coding RNA region in mouse [97]. Furthermore, one of the SNPs strongly associated with Parkinson's, rs356219, is located in the transcription factor YY1 binding site, which regulates expression of RP11-115D19.1, an antisense ncRNA in SNCA 3'-flanking region, which in turn negatively regulates SNCA expression [98]. ANRIL may be involved in development of atherosclerosis because the Chr9p21 atherosclerosis risk allele is associated with increased ANRIL expression [14].…”

Transcriptional regulation of the α-synuclein gene in human brain tissue

“…Thus, it can be assumed that at least some of these SNPs may alter the binding of TFs. This hypothesis was further strengthened with the recent finding that YY1 TFs exclusively bind to the protective allele of a SNP in the 3 -region of SNCA [22].…”

“…Given these results, it is more likely that SNPs associated with PD and elevated ␣-synuclein levels do not influence the binding of GATA2 and ZSCAN21. SNPs may have an impact on additional factors as described for YY1 [22], or the increased PD risk is due to other mechanisms, like alternative splicing of the mRNA, RNA stability, secondary structure or its intracellular transport.…”

Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases

“…REST is a master regulator of neuronal genes, whose protein abundance increases with stress and aging, but decreases with AD, frontotemporal dementia and dementia with Lewy bodies [88]. YY1 is a ubiquitous transcription factor previously noted to regulate several genes associated with neurodegenerative diseases including BACE1 and APP [89], SNCA [90], EAAT2 [91], MTOR and PPARGC1A [92]. …”