title: 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.
authors.affiliation: 1] Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Japan [2] Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Mizuta
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takafuji
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ando
authors.forename: Wataru
authors.initials: W
authors.lastname: Satake
authors.forename: Motoi
authors.initials: M
authors.lastname: Kanagawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shinohara
authors.forename: Chiyomi
authors.initials: C
authors.lastname: Ito
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Miho
authors.initials: M
authors.lastname: Murata
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D044466:Asian People; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D016372:RNA, Antisense / Q000096:biosynthesis* / Q000235:genetics; D022661:RNA, Untranslated / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D044465:White People; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016372:RNA, Antisense; D022661:RNA, Untranslated; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D051844:alpha-Synuclein