Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7

Tan, Jennifer Y.; Vance, Keith W.; Varela, Miguel A.; Sirey, Tamara; Watson, Lauren M.; Curtis, Helen J; Marinello, Martina; Alves, Sandro; Steinkraus, Bruno R.; Cooper, Sarah; Nesterova, Tatyana B.; Brockdorff, Neil; Fulga, Tudor A.; Brice, Alexis; Sittler, Annie; Oliver, Peter L.; Wood, Matthew; Ponting, Chris P.; Marques, Ana C.

doi:10.1038/nsmb.2902

Cited by 80 publications

(70 citation statements)

References 60 publications

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“…In a previous study, Tan and colleagues identified ATXN7L3B, also named lnc-SCA7, as a long noncoding RNA (25). Our work, using an antibody targeting the C terminus of ATXN7L3B, indicates that the ATXN7L3B gene encodes a 97-amino-acid protein of ϳ11 kDa.…”

Section: Discussionmentioning

confidence: 98%

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Atanassov

Lan

et al. 2016

Molecular and Cellular Biology

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fThe SAGA complex contains two enzymatic modules, which house histone acetyltransferase (HAT) and deubiquitinase (DUB) activities. USP22 is the catalytic subunit of the DUB module, but two adaptor proteins, ATXN7L3 and ENY2, are necessary for DUB activity toward histone H2Bub1 and other substrates. ATXN7L3B shares 74% identity with the N-terminal region of ATXN7L3, but the functions of ATXN7L3B are not known. Here we report that ATXN7L3B interacts with ENY2 but not other SAGA components. Even though ATXN7L3B localizes in the cytoplasm, ATXN7L3B overexpression increases H2Bub1 levels, while overexpression of ATXN7L3 decreases H2Bub1 levels. In vitro, ATXN7L3B competes with ATXN7L3 to bind ENY2, and in vivo, knockdown of ATXN7L3B leads to concomitant loss of ENY2. Unlike the ATXN7L3 DUB complex, a USP22-ATXN7L3B-ENY2 complex cannot deubiquitinate H2Bub1 efficiently in vitro. Moreover, ATXN7L3B knockdown inhibits migration of breast cancer cells in vitro and limits expression of ER target genes. Collectively, our studies suggest that ATXN7L3B regulates H2Bub1 levels and SAGA DUB activity through competition for ENY2 binding. U SP22 and the SAGA deubiquitinase (DUB) module are important for normal embryonic development (1), and alterations in the expression or structure of component proteins are linked to neurodegenerative disease and cancer (2, 3). The DUB module consists of a catalytic subunit, USP22, and two adaptor proteins, ATXN7L3 and ENY2, required for deubiquitinase activity and stability of the DUB module (4-6). Another protein, ATXN7, functions as a bridge to integrate the core DUB module into the greater SAGA complex (7,8) and has also been reported to affect DUB activity (6, 9, 10).ATXN7L3 contains a Sus1/ENY2-binding region in its N-terminal region, a ZnF-Sgf11 domain, and a SCA7 domain in its C-terminal region (6). The presence of ATXN7L3 is essential for the deubiquitinase activity of the DUB module. No stable complex could be formed in the absence of ATXN7L3 (6). Moreover, the ZnF-Sgf11 domain of ATXN7L3 plays a pivotal role in the enzymatic activity, but is dispensable for the assembly, of the DUB module (6). The ZnF-Sgf11 domain of ATXN7L3 is essential for DUB activity toward H2Bub1 in vitro (6). The ZnF-Sgf11 domain is required for ATXN7L3 binding to nucleosomal DNA (11), and the crystal structure of the DUB module reveals that an arginine cluster in the ZnF-Sgf11 domain directly interacts with ubiquitinated nucleosomes and H2A/H2B heterodimer (12).Loss of ATXN7L3B, a paralog of ATXN7L3, may also be associated with neurodegenerative disease (13), as three family members exhibiting loss of chromosome region 12q21, where ATXN7L3B lies, exhibited motor and cognitive deficiencies, as well as learning difficulties and cerebellar ataxia. ATXN7L3B and ATXN7L3 share 74% identity within their N-terminal ϳ60 amino acid residues (Fig. 1A), including the Sus1/ENY2-binding region (Fig. 1A, in red) (6, 14). Interestingly, a truncated form of ATXN7L3 that only contains amino acids 3 to 76 was shown by others to ...

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Section: Discussionmentioning

confidence: 98%

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Atanassov

Lan

et al. 2016

Molecular and Cellular Biology

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“…Other well-characterized examples of miRNA-lncRNA competitive interactions include lncRNA CHRF and miR-489 (crosstalking with Myd88 in the context of cardiac hypertrophy) [71], the liver cancer-associated lncRNA HULC and miR-372 [which participate in an autoregulatory loop that involves cAMP response element binding protein (CREB)-dependent transcriptional upregulation of HULC following inhibition of miR-372 activity] [72], the crosstalk between ATXN7 and the lnc-SCA7 depending on miR-124 binding in spinocerebellar ataxia [73], or the imprinted H19 lncRNA (which is expressed during skeletal muscle cell differentiation) and let-7. H19 sponges let-7 and alters the expression of let-7 target transcripts [such as Dicer and high mobility group AT-hook 2 (HMGA2)], causes precocious muscle differentiation in overexpressing cultures [74], and is involved in insulin signaling and glucose regulation pathways [75].…”

Section: A Widespread Regulation?mentioning

confidence: 99%

RNA–RNA interactions in gene regulation: the coding and noncoding players

Guil

Esteller

2015

Trends in Biochemical Sciences

226

165

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“…Both computational and experimental evidence support the extensive targeting of lncRNAs by miRNAs (Paraskevopoulou et al 2013). While a small number of lncRNAs are currently known to function as ceRNAs (Cesana et al 2011;Fan et al 2013;Wang et al 2013;Tan et al 2014), the full extent of lncRNAs possessing miRNA-dependent regulatory roles remains to be determined (Ulitsky and Bartel 2013).…”

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confidence: 99%

Extensive microRNA-mediated crosstalk between lncRNAs and mRNAs in mouse embryonic stem cells

et al. 2015

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Recently, a handful of intergenic long noncoding RNAs (lncRNAs) have been shown to compete with mRNAs for binding to miRNAs and to contribute to development and disease. Beyond these reports, little is yet known of the extent and functional consequences of miRNA-mediated regulation of mRNA levels by lncRNAs. To gain further insight into lncRNA-mRNA miRNA-mediated crosstalk, we reanalyzed transcriptome-wide changes induced by the targeted knockdown of over 100 lncRNA transcripts in mouse embryonic stem cells (mESCs). We predicted that, on average, almost one-fifth of the transcript level changes induced by lncRNAs are dependent on miRNAs that are highly abundant in mESCs. We validated these findings experimentally by temporally profiling transcriptome-wide changes in gene expression following the loss of miRNA biogenesis in mESCs. Following the depletion of miRNAs, we found that >50% of lncRNAs and their miRNA-dependent mRNA targets were up-regulated coordinately, consistent with their interaction being miRNA-mediated. These lncRNAs are preferentially located in the cytoplasm, and the response elements for miRNAs they share with their targets have been preserved in mammals by purifying selection. Lastly, miRNA-dependent mRNA targets of each lncRNA tended to share common biological functions. Post-transcriptional miRNA-mediated crosstalk between lncRNAs and mRNA, in mESCs, is thus surprisingly prevalent, conserved in mammals, and likely to contribute to critical developmental processes.

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Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7

Cited by 80 publications

References 60 publications

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

RNA–RNA interactions in gene regulation: the coding and noncoding players

Extensive microRNA-mediated crosstalk between lncRNAs and mRNAs in mouse embryonic stem cells

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