5′UTR-mediated regulation of Ataxin-1 expression

Manek, Rachna; Nelson, Tiffany Schyler; Tseng, Elizabeth; Rodríguez-Lebrón, Edgardo

doi:10.1016/j.nbd.2019.104564

Cited by 22 publications

(16 citation statements)

References 35 publications

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“…Therefore, we were intrigued to find that ATXN1 contains one of the longest 5 ′ UTRs found in humans. We report that ATXN1's long 5 ′ UTR negatively regulates its expression by decreasing ATXN1's mRNA stability, a mechanism independent of the recently reported translational inhibition via upstream AUGs and alternative splicing in cerebellar and cortical tissues (Manek et al 2019).…”

Section: Discussionmentioning

confidence: 65%

“…1E). While a recent study found that ATXN1's 5 ′ UTR regulates its translation via out-of-frame upstream AUGs (Manek et al 2019), we were in parallel interested in studying the effect the 5 ′ UTR may have on mRNA levels. To investigate whether the 5 ′ UTR has an effect on mRNA stability, we measured luciferase RNA levels and found that compared with the control, ATXN1's 5 ′ UTR significantly decreased luciferase RNA levels (Fig.…”

Section: Atxn1 Contains a Long 5 ′ Utr That Negatively Regulates Its Expressionmentioning

confidence: 99%

“…5 ′ UTRs are mainly known for their importance in translational regulation by dampening translation via upstream open reading frames and secondary structures (Mignone et al 2002). Indeed, a recent study showed that ATXN1's 5 ′ UTR is involved in its translational control (Manek et al 2019). Studies have also shown that 5 ′ UTRs can provide a platform for miRNAs to bind and regulate their target gene expression via a variety of other posttranscriptional mechanisms (Ørom et al 2008;Moretti et al 2010;Dewing et al 2012;Zhou and Rigoutsos 2014).…”

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confidence: 99%

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miR760 regulates ATXN1 levels via interaction with its 5′ untranslated region

et al. 2020

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Identifying modifiers of dosage-sensitive genes involved in neurodegenerative disorders is imperative to discover novel genetic risk factors and potential therapeutic entry points. In this study, we focus on Ataxin-1 (ATXN1), a dosage-sensitive gene involved in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). While the precise maintenance of ATXN1 levels is essential to prevent disease, the mechanisms that regulate ATXN1 expression remain largely unknown. We demonstrate that ATXN1's unusually long 5 ′ untranslated region (5 ′ UTR) negatively regulates its expression via posttranscriptional mechanisms. Based on recent reports that microRNAs (miRNAs) can interact with both 3 ′ and 5 ′ UTRs to regulate their target genes, we identify miR760 as a negative regulator that binds to a conserved site in ATXN1's 5 ′ UTR to induce RNA degradation and translational inhibition. We found that delivery of Adeno-associated virus (AAV)-expressing miR760 in the cerebellum reduces ATXN1 levels in vivo and mitigates motor coordination deficits in a mouse model of SCA1. These findings provide new insights into the regulation of ATXN1 levels, present additional evidence for miRNA-mediated gene regulation via 5 ′ UTR binding, and raise the possibility that noncoding mutations in the ATXN1 locus may act as risk factors for yet to be discovered progressive ataxias.

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Section: Discussionmentioning

confidence: 65%

Section: Atxn1 Contains a Long 5 ′ Utr That Negatively Regulates Its Expressionmentioning

confidence: 99%

mentioning

confidence: 99%

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miR760 regulates ATXN1 levels via interaction with its 5′ untranslated region

et al. 2020

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“…Interestingly, a nested ORF within the canonical ATXN1 CDS was previously shown to be translated as a stable protein (Bergeron et al, 2013). Further experimental work will be required to decipher the apparently complex mechanisms of this locus, which is linked to cerebellar ataxias, and recent research indicates that translational control is at least in part mediated by alternative splicing in the 5’ UTR (Manek et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

A community-driven roadmap to advance research on translated open reading frames detected by Ribo-seq

Mudge

Ruiz-Orera

Prensner

et al. 2021

Preprint

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Ribosome profiling (Ribo-seq) has catalyzed a paradigm shift in our understanding of the translational vocabulary of the human genome, discovering thousands of translated open reading frames (ORFs) within long non-coding RNAs and presumed untranslated regions of protein-coding genes. However, reference gene annotation projects have been circumspect in their incorporation of these ORFs due to uncertainties about their experimental reproducibility and physiological roles. Yet, it is indisputable that certain Ribo-seq ORFs make stable proteins, others mediate gene regulation, and many have medical implications. Ultimately, the absence of standardized ORF annotation has created a circular problem: while Ribo-seq ORFs remain unannotated by reference biological databases, this lack of characterisation will thwart research efforts examining their roles. Here, we outline the initial stages of a community-led effort supported by GENCODE / Ensembl, HGNC and UniProt to produce a consolidated catalog of human Ribo-seq ORFs.

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“…Mammalian miRNA-guided repression generally involves binding of the Argonaute (AGO)-miRNA complex (RNA-induced silencing complex [RISC]) to miRNA target sites together with recruitment of TNRC6 proteins and deadenylase complexes (CCR4-NOT and PAN2-PAN3) to modulate mRNA translation and turnover with miRNA target sites located predominantly in the 3 ′ UTR (Bartel 2018). However, the investigators were intrigued by the lengthy ATXN1 5 ′ UTR (971 bp) and the recent report of alternative splicing of exons 2 and 3 in the 5 ′ UTR as well as the presence of multiple upstream open reading frames (uORFs) (Manek et al 2020).…”

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confidence: 99%

UTteR control through miRs: fine-tuning ATXN1 levels to prevent ataxia

Xie

Swanson

2020

Genes Dev.

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Pathomechanistic studies of neurodegenerative diseases have documented the toxic effects of mutant protein expression, misfolding, and aggregation. However, alterations in the expression of the corresponding wild-type (WT) gene, due to either variations in copy number or transcriptional regulation, have also been linked to Alzheimer's and Parkinson's diseases. Another striking example of this mutant and WT duality is spinocerebellar ataxia type 1 (SCA1) caused by an ATXN1 polyglutamine protein, although subtle variations in WT AXTN1 levels also lead to ataxia. In this issue of Genes & Development, Nitschke and colleagues (pp. 1147–1160) delve into posttranscriptional events that fine-tune ATXN1 expression and uncover a key role for 5′ untranslated region (5′ UTR)–miR760 interactions. Thus, this study not only provides significant insights into the complexities of modulating the expression of a dosage-sensitive gene but also highlights the critical importance of identifying noncoding polymorphisms as disease risk factors.

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5′UTR-mediated regulation of Ataxin-1 expression

Cited by 22 publications

References 35 publications

miR760 regulates ATXN1 levels via interaction with its 5′ untranslated region

miR760 regulates ATXN1 levels via interaction with its 5′ untranslated region

A community-driven roadmap to advance research on translated open reading frames detected by Ribo-seq

UTteR control through miRs: fine-tuning ATXN1 levels to prevent ataxia

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