Long non-coding RNA-dependent transcriptional regulation in neuronal development and disease

Clark, Brian S.; Blackshaw, Seth

doi:10.3389/fgene.2014.00164

Cited by 136 publications

(121 citation statements)

References 219 publications

(368 reference statements)

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“…lncRNAs are RNAs . 200 nt that do not contain an open reading frame; although their biological meaning and function still need to be elucidated, ample evidence, including specific subcellular localization, tissue specificity, and association with disease, indicates that they may be essential regulators of cell function (27)(28)(29). The importance of lncRNAs in MS is highlighted by recent studies showing that various SNPs associated with MS in GWAS are located in genomic regions that code for lncRNAs (30) or regulate lncRNA expression in cis in human monocytes (31).…”

Section: Discussionmentioning

confidence: 99%

Novel Insights into the Multiple Sclerosis Risk Gene ANKRD55

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et al. 2016

The Journal of Immunology

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An intronic variant in ANKRD55, rs6859219, is a genetic risk factor for multiple sclerosis, but the biological reasons underlying this association are unknown. We characterized the expression of ANKRD55 in human PBMCs and cell lines. Three ANKRD55 transcript variants (Ensembl isoforms 001, 005, and 007) could be detected in PBMCs and CD4+ T cells but were virtually absent in CD8+, CD14+, CD19+, and CD56+ cells. Rs6859219 was significantly associated with ANKRD55 transcript levels in PBMCs and CD4+ T cells and, thus, coincides with a cis-expression quantitative trait locus. The processed noncoding transcript 007 was the most highly expressed variant in CD4+ T cells, followed by 001 and 005, respectively, but it was not detected in Jurkat, U937, and SH-SY5Y cell lines. Homozygotes for the risk allele produced more than four times more transcript copies than did those for the protective allele. ANKRD55 protein isoforms 005 and 001 were predominantly located in the nucleus of CD4+ T cells and Jurkat and U937 cells. ANKRD55 was produced by primary cultures of murine hippocampal neurons and microglia, as well as by the murine microglial cell line BV2, and it was induced by inflammatory stimuli. ANKRD55 protein was increased in the murine mouse model of experimental autoimmune encephalomyelitis. Flow cytometric analysis of CNS-infiltrating mononuclear cells showed that CD4+ T cells and monocytes expressed ANKRD55 in experimental autoimmune encephalomyelitis mice, with the higher fluorescence intensity found in CD4+ cells. A low percentage of microglia also expressed ANKRD55. Together, these data support an important role for ANKRD55 in multiple sclerosis and neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Novel Insights into the Multiple Sclerosis Risk Gene ANKRD55

Lapuente

Feliú

Ugidos

et al. 2016

The Journal of Immunology

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“…Recently, intron-retaining transcripts have been attracting much attention as non-coding RNAs that play a physiological role (Wong et al 2013). In particular, many non-coding RNAs have been identified in human brain (Barry 2014;Clark and Blackshaw 2014). It is suggested that non-coding transcripts containing exon 1a or 41e play a physiological role in neurons.…”

Section: Discussionmentioning

confidence: 99%

Neuronal SH-SY5Y cells use the C-dystrophin promoter coupled with exon 78 skipping and display multiple patterns of alternative splicing including two intronic insertion events

et al. 2015

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Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by mutations in the dystrophin gene. One-third of DMD cases are complicated by mental retardation. Here, we used reverse transcription PCR to analyze the pattern of dystrophin transcripts in neuronal SH-SY5Y cells. Among the three alternative promoters/first exons at the 5'-end, only transcripts containing the brain cortex-specific C1 exon could be amplified. The C-transcript appeared as two products: a major product of the expected size and a minor larger product that contained the cryptic exon 1a between exons C1 and 2. At the 3'-end there was complete exon 78 skipping. Together, these findings indicate that SH-SY5Y cells have neuron-specific characteristics with regard to both promoter activation and alternative splicing. We also revealed partial skipping of exons 9 and 71. Four amplified products were obtained from a fragment covering exons 36-41: a strong expected product, two weak products lacking either exon 37 or exon 38, and a second strong larger product with a 568-bp insertion between exons 40 and 41. The inserted sequence matched the 3'-end of intron 40 perfectly. We concluded that a cryptic splice site was activated in SH-SY5Y cells to create the novel, unusually large, exon 41e (751 bp). In total, we identified seven alternative splicing events in neuronal SH-SY5Y cells, and calculated that 32 dystrophin transcripts could be produced. Our results may provide clues in the analysis of transcriptype-phenotype correlations as regards mental retardation in DMD.

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“…Other than housekeeping non-coding RNAs (ribosomal RNAs, transfer RNAs, and small nuclear RNAs), whose biological functions have been well defined, regulatory non-coding RNAs (siRNAs, microRNAs, and long non-coding RNAs) have recently shown to be actively involved in physiological regulations (Djebali, Davis et al 2012, Kornfeld andBruning 2014). Further, lncRNAs have been shown to perform transcriptional regulation through interaction with transcription factors in different tissues (Clark andBlackshaw 2014, Herriges, Swarr et al 2014). …”

Section: Car and Pxr Have Been Reported To Regulate Expression Of Spementioning

confidence: 99%

A Transcriptional Regulatory Network Containing Nuclear Receptors and Long Noncoding RNAs Controls Basal and Drug-Induced Expression of Cytochrome P450s in HepaRG Cells

et al. 2018

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Cytochrome P450 (P450) enzymes are responsible for biotransformation of xenobiotics, including environmental toxicants and drugs. Expression of P450s can directly affect drug metabolism, resulting in various outcome in either therapeutic efficacy or adverse effects. Nuclear receptors are a class of transcription factors that can regulate expression of P450s at both basal and drug‐induced levels. Some long non‐coding RNAs (lncRNAs) near a transcription factor are found to participate in the regulatory functions of the transcription factors in either promotion or repression manner. The aim of this study is to determine whether there is a transcriptional regulatory network containing nuclear receptors and lncRNAs controlling both basal and drug‐induced expression of P450s in liver cells. Four nuclear receptors, hepatocyte nuclear factor 1a (HNF1a), hepatocyte nuclear factor 4a (HNF4a), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) as well as two lncRNAs, HNF1a‐antisense 1 (HNF1a‐AS1) and HNF4a‐antisense 1 (HNF4a‐AS1) were examined in control of basal and drug‐induced expression of 8 different P450 enzymes. Small interfering RNAs (siRNAs) were applied to knock down the nuclear receptors and lncRNAs in HepaRG cells with or without treatment of phenobarbital or rifampicin. Expression of the nuclear receptors, lncRNAs, and P450s was measured by RT‐PCR and Western blots. Knocking down of HNF1a or HNF4a affected basal expression of numerous P450s as well as CAR and PXR, and also impaired phenobarbital or rifampicin induced expression of several P450s, which may be due to decreased CAR/PXR expression. Moreover, HNF4a knockdown was able to decrease HNF1a expression and showed more potent effect than HNF1a knockdown. Knocking down of CAR or PXR only affected basal and induced expression of their target P450s without affecting expression of HNF1a or HNF4a. These data suggested the existence of a regulatory network in controlling P450 expression in an order through HNF4a to HNF1a to CAP/PXR. Expression of HNF1a‐AS1 and HNF4a‐AS1 is largely dependent on expression of their nearby coding gene HNF1a and HNF4a. Moreover, HNF4a knockdown depleted expression of both lncRNAs, but HNF1a knockdown only depleted HNF1a‐AS1 expression. Knocking down of HNF1a‐AS1 showed a similar regulation trend on the P450s compared to HNF1a or HNF4a knockdown, indicating involvement of this lncRNA in the regulation of P450s. However, knocking down of HNF4a‐AS1 showed an opposite regulation trend compared to HNF1a or HNF4a knockdown, indicating that HNF4a‐AS1 may play an inhibitory role in the HNF4a function. Altogether, out study concludes that there is a transcription regulatory network among the different nuclear receptors and lncRNAs in the regulation of both basal and drug‐induced expression of P450s in liver cells. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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Long non-coding RNA-dependent transcriptional regulation in neuronal development and disease

Cited by 136 publications

References 219 publications

Novel Insights into the Multiple Sclerosis Risk Gene ANKRD55

Novel Insights into the Multiple Sclerosis Risk Gene ANKRD55

Neuronal SH-SY5Y cells use the C-dystrophin promoter coupled with exon 78 skipping and display multiple patterns of alternative splicing including two intronic insertion events

A Transcriptional Regulatory Network Containing Nuclear Receptors and Long Noncoding RNAs Controls Basal and Drug-Induced Expression of Cytochrome P450s in HepaRG Cells

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