PARTICLE triplexes cluster in the tumor suppressor WWOX and may extend throughout the human genome

Abstract

The long non-coding RNA PARTICLE (Gene PARTICL- ‘Promoter of MAT2A-Antisense RadiaTion Induced Circulating LncRNA) partakes in triple helix (triplex) formation, is transiently elevated following low dose irradiation and regulates transcription of its neighbouring gene - Methionine adenosyltransferase 2A. It now emerges that PARTICLE triplex sites are predicted in many different genes across all human chromosomes. In silico analysis identified additional regions for PARTICLE triplexes at >1600 genomic locations. Multiple PARTICLE triplexes are clustered predominantly within the human and mouse tumor suppressor WW Domain Containing Oxidoreductase (WWOX) gene. Surface plasmon resonance diffraction and electrophoretic mobility shift assays were consistent with PARTICLE triplex formation within human WWOX with high resolution imaging demonstrating its enrichment at this locus on chromosome 16. PARTICLE knockdown and over-expression resulted in inverse changes in WWOX transcripts levels with siRNA interference eliminating PARTICLEs elevated transcription to irradiation. The evidence for a second functional site of PARTICLE triplex formation at WWOX suggests that PARTICLE may form triplex-mediated interactions at multiple positions in the human genome including remote loci. These findings provide a mechanistic explanation for the ability of lncRNAs to regulate the expression of numerous genes distributed across the genome.

The long non-coding RNA PARTICLE is associated with WWOX and the absence of FRA16D breakage in osteosarcoma patients

“…51741) [ 17 ]. It has also been demonstrated that PARTICLE overexpression leads to a reduction in WWOX expression [ 18 ].…”

“…PARTICLE forms a triplex within the MAT2A promoter and operates an active feedback silencing loop limiting the upregulation of MAT2A in response to low dose radiation [ 15 ]. In contrast to earlier models that showed PARTICLEs repressive ability was, typical of most lncRNAs, restricted to a specific gene at a local (usually in cis ) level, it has been recently discovered that PARTICLE over-expression enhances trimethylation of histone H3 lysine 27 across the human genome with specific enrichment within WWOX [ 17 , 18 ]. In contrast, diminished hyper-methylation of a WWOX promoter CpG island was evident upon PARTICLE knockdown [ 17 ].…”

PARTICLE − The RNA podium for genomic silencers

“…Efforts of late to assign lncRNAs on the basis of whether they regulate local gene expression in cis or leave the site of transcription and perform effects in trans assumes an either/or scenario for functional classification purposes (Kopp & Mendell, ). In regard to PARTICLE , evidence has been gathered providing proof of its capability for local as well as distant regulatory effects potentially genome‐wide in human as well as in mouse (O'Leary, Smida et al, ). PARTICLE is transcribed in an antisense direction as a 1432 bp transcript within the MAT2A gene promoter on chromosome 2p11.2.…”

“…This would suggest that H3K27me3 modifying enzymes might be guided to specific PARTICLE triplex sites to exert their function. PARTICLE is capable of enhancing the histone repressive modification mark across the human genome and specifically within MAT2A and WWOX tumor suppressor genes presumably via its provision of a triplex binding platform (O'Leary, Smida et al, ). Combining the analytical integration power of INGENUITY using ChIP‐seq H3K27me3 data and TDF evidence revealed the significance of the PARTICLE triplex podium and genes associated with malignancy.…”

WWOX Phosphorylation, Signaling, and Role in Neurodegeneration

“…WWOX is composed of 9 exons with an open reading frame (ORF) of 1245 base pairs long, encoding a 414-amino-acid (46 kDa) protein. WWOX gene possesses multiple long non-coding RNA PARTICLE (Gene PARTICL - ‘ P romoter of MAT2A - A ntisense R adia T ion I nduced C irculating L ncRNA) triplex clusters, suggesting its control of gene expression in the genome ( O’Leary et al, 2017 ). WWOX protein possesses two N -terminal WW domains, a nuclear localization signal between the WW domains, a C -terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a proapoptotic C -terminal tail termed D3 ( Bednarek et al, 2000 ; Ried et al, 2000 ; Chang et al, 2001 ; Hong et al, 2007 ; Lin et al, 2011 ; Abu-Remaileh and Aqeilan, 2015 , Abu-Remaileh et al, 2015 ; Huang and Chang, 2018 ).…”