Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements

Torres, Manon; Becquet, Denis; Blanchard, Marie-Pierre; Guillen, Séverine; Boyer, Brigitte; Moreno, Mathias; Franc, Jean‐Louis; François‐Bellan, Anne‐Marie

doi:10.7554/elife.14837

Cited by 42 publications

(52 citation statements)

References 41 publications

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“…Furthermore, these mice also present with abnormal rhythmic fluctuations of daily activity, which is in line with the recently reported role for Neat1 in the control of circadian genes (Torres et al, 2016). Behavioural features detected in these mice, i.e.…”

Section: Discussionsupporting

confidence: 89%

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Kukharsky

Ninkina

et al. 2019

Preprint

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NEAT1 is a highly and ubiquitously expressed long non-coding RNA (lncRNA) which serves as an important regulator of cellular stress response. However, the physiological role of NEAT1 in the central nervous system (CNS) is still poorly understood. In the current study, we addressed this by characterising the CNS function in the Neat1 knockout mouse model (Neat1 -/mice), using a combination of behavioural phenotyping, electrophysiology and expression analysis. RNAscope® in situ hybridisation revealed that in wild-type mice, Neat1 is expressed evenly across the CNS, with high expression in glial cells and low expression in neurons. Loss of Neat1 in mice results in an inadequate reaction to physiological stress manifested as hyperlocomotion and panic escape response. In addition, Neat1 -/mice display deficits in social interaction and rhythmic patterns of activity but retain normal motor function and memory. Neat1 -/mice do not present with neuronal loss, overt neuroinflammation or gross synaptic dysfunction in the brain. However, cultured Neat1 -/neurons are characterised by hyperexcitability and dysregulated calcium homeostasis, and stress-induced neuronal activity is also augmented in Neat1 -/mice in vivo. Gene expression analysis showed that Neat1 may act as a weak positive regulator of multiple genes in the brain. Furthermore, loss of Neat1 affects alternative splicing of genes important for the CNS function and implicated in neurological diseases. Overall, our data suggest that Neat1 is involved in stress signaling in the brain and fine-tunes the CNS functions to enable adaptive behaviour in response to physiological stress.

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Section: Discussionsupporting

confidence: 89%

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Kukharsky

Ninkina

et al. 2019

Preprint

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“…35 These results obtained on endogenous mRNA, together with results obtained with a reporter gene, allow to conclude that paraspeckles participate in the post-transcriptional control of rhythmic gene expression (Fig. 2).…”

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confidence: 89%

“…Paraspeckles through their circadian expression, could then control circadian expression pattern of a reporter gene containing IRAlu elements in 3'-UTR. 35 We then asked whether this circadian post-transcriptional regulation exerted by paraspeckle bodies applies to endogenous genes. To address this issue, it was necessary to determine which mRNA are associated with paraspeckle bodies in the nucleus of GH4C1 cells.…”

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confidence: 99%

“…In addition we showed that circadian expression of these different components leads to rhythmic variations in paraspeckle number within the cells. 35 Thanks to their circadian expression pattern and given their presumed functions in gene expression through corresponding mRNA nuclear retention, we asked whether paraspeckle bodies can rhythmically retain RNAs in the nucleus leading to a rhythmic expression of the corresponding gene. This hypothesis was first tested with a reporter gene.…”

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confidence: 99%

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Paraspeckles as rhythmic nuclear mRNA anchorages responsible for circadian gene expression

Torres

Becquet

Blanchard

et al. 2017

Nucleus

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Circadian clocks regulate rhythmic gene expression levels by means of mRNA oscillations that are mainly driven by post-transcriptional regulation. We identified a new post-transcriptional mechanism, which involves nuclear bodies called paraspeckles. Major components of paraspeckles including the long noncoding RNA Neat1, which is the structural component, and its major protein partners, as well as the number of paraspeckles, follow a circadian pattern in pituitary cells. Paraspeckles are known to retain within the nucleus RNAs containing inverted repeats of Alu sequences. We showed that a reporter gene in which these RNA duplex elements were inserted in the 3'-UTR region displayed a circadian expression. Moreover, circadian endogenous mRNA associated with paraspeckles lost their circadian pattern when paraspeckles were disrupted. This work not only highlights a new paraspeckle-based post-transcriptional mechanism involved in circadian gene expression but also provides the list of all mRNA associated with paraspeckles in the nucleus of pituitary cells.

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“…Since then, PS have been implicated in gene expression regulation and in the maintenance of DNA integrity in response to endogenous and exogenous forms of stresses (Chen and Carmichael 2009;Hirose et al 2014;Imamura et al 2014;Choudhry et al 2014;Adriaens et al 2016;Mello et al 2017;Ahmed et al 2018;Lellahi et al 2018). This may occur through their interaction with the RNA interference (RNAi) machinery and with micro-RNAs (Jiang et al 2017;Li et al 2018;Shuaib et al 2019), or via the modulation of transcriptional and posttranscriptional regulators (Hirose et al 2014;Hu et al 2015;Kawaguchi et al 2015;Torres et al 2016;Morchikh et al 2017;Wang et al 2018;Hupalowska et al 2018). Importantly, the generation of Neat1-deficient mice has highlighted a critical role for this lncRNA in the formation of a functional lactating mammary gland and corpus luteum (Nakagawa et al 2014;Standaert et al 2014;Adriaens et al 2016).…”

Section: Graphical Abstract Introductionmentioning

confidence: 99%

The lncRNA NEAT1_1 is dispensable for normal tissue homeostasis and cancer cell growth

Adriaens¹,

Rambow²,

Bervoets³

et al. 2019

Preprint

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NEAT1 is one of the most studied lncRNAs, in part because its silencing in mice causes defects in mammary gland development and corpus luteum formation, and protects them from skin cancer development. Moreover, depleting NEAT1 in established cancer cell lines reduces growth and sensitizes cells to DNA damaging agents. However, NEAT1 produces two isoforms and because the short isoform, NEAT1_1, completely overlaps the 5' part of the long NEAT1_2 isoform, the respective contributions of each of the isoforms to these phenotypes has remained unclear. Whereas NEAT1_1 is highly expressed in most tissues, NEAT1_2 is the central architectural component of paraspeckles, which are nuclear bodies that assemble in specific tissues and cells exposed to various forms of stress. Using dual RNA-FISH to detect both NEAT1_1 outside of paraspeckles and NEAT1_2/NEAT1 inside this nuclear body, we report herein that NEAT1_1 levels are dynamically regulated during the cell cycle and targeted for degradation by the nuclear RNA exosome. Unexpectedly, however, cancer cells engineered to lack NEAT1_1, but not NEAT1_2, do not exhibit cell cycle defects. Moreover, Neat1_1-specific knockout mice do not exhibit the phenotypes observed in Neat1-deficient mice. We propose that NEAT1 functions are mainly, if not exclusively, attributable to NEAT1_2 and, by extension, to paraspeckles.

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Circadian RNA expression elicited by 3’-UTR IRAlu-paraspeckle associated elements

Cited by 42 publications

References 41 publications

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Paraspeckles as rhythmic nuclear mRNA anchorages responsible for circadian gene expression

The lncRNA NEAT1_1 is dispensable for normal tissue homeostasis and cancer cell growth

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