Mechanisms of Long Non-Coding RNAs in the Assembly and Plasticity of Neural Circuitry

Wang, Yuzhuo; Wang, Junbao; Liu, Ying; Zhou, Yan

doi:10.3389/fncir.2017.00076

Cited by 42 publications

(31 citation statements)

References 161 publications

(175 reference statements)

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“…LncRNAs play an important role in fine-tuning the functions specific for different cell types, and their activity might be especially important in the adult nervous system. Indeed, lncRNAs have been reported to regulate critical processes in the developing and adult brain, including cell differentiation, neurite elaboration and synaptogenesis (Briggs et al, 2015;Wang et al, 2017). NEAT1 is an abundant lncRNA known to be expressed in the mammalian CNS however its role in the CNS under basal conditions and under conditions of physiological stress remained largely unknown.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

Kukharsky

Ninkina

et al. 2019

Preprint

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“…LncRNA are longer than 200 base pairs (bp) with limited or no protein coding potential (14) and while they have not been functionally fully characterized yet, they were shown to participate in chromatin remodeling (15), transcriptional and post-transcriptional regulation (16), and in sequestering miRNA (17;18). LncRNA have also been implicated in the plasticity of neuronal circuity (19) and in neurodegenerative and neuropsychiatric disorders including substance abuse and alcohol dependence (20;21); the potential role of lncRNA in the etiology of AUD was also further supported by several recent alcohol-related genome-wide association scans (GWAS) (22;23). Due to the complex nature of lncRNA functions, the relationship between lncRNA and alcohol consumption has been understudied; while miRNA roles in the control of gene expression and functions in the brains of subjects with AUD have been reported (2;24-27), to our knowledge the interactions between lncRNA and protein coding genes (PCG) are still largely undescribed.…”

Section: Introductionmentioning

confidence: 99%

Assessing the role of long-noncoding RNA in nucleus accumbens in subjects with alcohol dependence

McMichael

Drake

Vornholt

et al. 2019

Preprint

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Recently, long noncoding RNA (lncRNA) were implicated in the etiology of alcohol dependence (AD). As lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step towards understanding lncRNA functions in AD. To that end, we profiled the expression of lncRNA and protein coding genes (PCG) in nucleus accumbens (NAc) from 41 subjects with AD and 41 controls. At false discovery rate (FDR) of 5%, we identified 69 and 309 differentially expressed lncRNA and PCG genes, respectively. Using co-expression network analyses, we identified three lncRNA and five PCG modules significantly correlated with AD at Bonferroni adj. p≤0.05. To better understand lncRNA functions, we integrated the lncRNA and PCG hubs from the significant AD modules; at FDR of 5%, we identified 3 151 positive and 2 255 negative correlations supporting the functional role of lncRNA in the development of AD. Gene enrichment analysis revealed that PCG significantly correlated with lncRNA are, among others, enriched for neuronal and immune related processes. To highlight the mechanisms, by which genetic variants contribute to AD, we integrated lncRNA and PCG hubs with genome-wide SNP data. At FDR≤0.3, we identified 276 expression quantitative trait loci (eQTL), affecting the expression of 20 and 256 lncRNA and PCG hubs, respectively. Our study is the first to profile lncRNA expression in nucleus accumbens in a large postmortem alcohol brain sample and our results may provide novel insights into the regulation of the brain transcriptome across disease.

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“…Although divergent lncRNAs are prevalent in both embryonic and adult nervous system, only a few functional divergent lncRNAs have been characterized, including roles of Emx2os in regulating the expressions of their neighboring protein-coding transcripts Emx2, an essential cortical RGPC gene (Noonan et al, 2003;Spigoni et al, 2010). Furthermore, these are largely in vitro studies and it's still lack of in vivo evidence showing the significance of divergent lncRNAs in cortical neuronal differentiation (Wang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA LncKdm2b regulates cortical neuronal differentiation by cis-activating Kdm2b

Shen

Zhang

et al. 2019

Protein Cell

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The mechanisms underlying spatial and temporal control of cortical neurogenesis of the brain are largely elusive. Long non-coding RNAs (lncRNAs) have emerged as essential cell fate regulators. Here we found LncKdm2b (also known as Kancr), a lncRNA divergently transcribed from a bidirectional promoter of Kdm2b, is transiently expressed during early differentiation of cortical projection neurons. Interestingly, Kdm2b's transcription is positively regulated in cis by LncKdm2b, which has intrinsic-activating function and facilitates a permissive chromatin environment at the Kdm2b's promoter by associating with hnRNPAB. Lineage tracing experiments and phenotypic analyses indicated LncKdm2b and Kdm2b are crucial in proper differentiation and migration of cortical projection neurons. These observations unveiled a lncRNA-dependent machinery in regulating cortical neuronal differentiation.

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Mechanisms of Long Non-Coding RNAs in the Assembly and Plasticity of Neural Circuitry

Cited by 42 publications

References 161 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

Assessing the role of long-noncoding RNA in nucleus accumbens in subjects with alcohol dependence

Long non-coding RNA LncKdm2b regulates cortical neuronal differentiation by cis-activating Kdm2b

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