Interplay between coding and exonic splicing regulatory sequences

Fontrodona, Nicolas; Aubé, Fabien; Claude, Jean‐Baptiste; Polvèche, Hélène; Lemaire, Sébastien; Tranchevent, Léon-Charles; Modolo, Laurent; Mortreux, Franck; Bourgeois, Cyril F.; Auboeuf, Didier

doi:10.1101/334839

Cited by 2 publications

(1 citation statement)

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“…It has been reported that RBPs, such as Embryonic lethal abnormal vision like protein family (ELVAL), TAR DNA-binding protein 43 (TDP43), eukaryotic initiation factor 2 (eIF2α)W2, play pivotal regulatory roles in the development of neurodegenerative diseases including AD [8][9][10] . TRA2A is located at 7p15.3 and plays an important role in the splicing regulatory process of pre-mRNA [11] . TRA2A is highly expressed in the neurodegenerative disease, fragile Xassociated tremor/ataxia syndrome (FXTAS).…”

Section: Abstract Blood Brain Barrier Alzheimer's Disease Tra2a LImentioning

confidence: 99%

TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

et al. 2020

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The blood-brain barrier (BBB) plays a pivotal role in maintenance and regulation of the neural microenvironment. The occurrence of BBB disruption is the pathological change of early Alzheimer's disease (AD). RNA-binding proteins and long non-coding RNAs are involved in the regulation of BBB permeability. Our study was performed to demonstrate TRA2A/LINC00662/ELK4 axis in regulating BBB permeability in AD microenvironment. In Aβ1-42-incubated microvascular endothelial cells (ECs) of BBB model in vitro, TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased the BBB permeability via upregulating the expressions of tight junction-related proteins. ELK4 was lower expressed in BBB model in vitro in AD microenvironment. LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. The downregulated ELK4 increased the permeability of BTB by increasing the tight junctionrelated proteins expressions. TRA2A/LINC00662/ELK4 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment, which may provide a novel target for the therapy of AD.

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Section: Abstract Blood Brain Barrier Alzheimer's Disease Tra2a LImentioning

confidence: 99%

TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

et al. 2020

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Interplay between gene nucleotide composition bias and splicing

Lemaire

Fontrodona

Claude

et al. 2019

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1To characterize the rules governing exon recognition during splicing, we analysed dozens of RNA-seq 2 datasets and identified ~3,200 GC-rich exons and ~4,000 AT-rich exons whose inclusion depends on 3 different sets of splicing factors. We show that GC-rich exons have predicted RNA secondary 4 structures at 5′-ss, and are dependent on U1 snRNP-associated proteins. In contrast, AT-rich exons 5 have a large number of branchpoints and SF1-or U2AF2-binding sites and are dependent on U2 6 snRNP-associated proteins. Nucleotide composition bias also influences local chromatin 7 organization, with consequences for exon recognition during splicing. As the GC content of exons 8 correlates with that of their hosting genes, isochores and topologically-associated domains, we 9 propose that regional nucleotide composition bias leaves a local footprint at the exon level and 10 induces constraints during splicing that can be alleviated by local chromatin organization and 11 recruitment of specific splicing factors. Therefore, nucleotide composition bias establishes a direct 12 link between genome organization and local regulatory processes, like alternative splicing. 13 14 Keywords: splicing; genomic; chromatin organization; nucleotide composition bias 15 genes than AT-rich isochores, and genes in GC-rich isochores contain smaller introns than genes in 1 AT-rich isochores [21][22][23] . It has been proposed that splicing of short introns in a GC-rich context may 2 occur through the intron definition model, while the splicing of large introns in an AT-rich context 3 may occur through the exon definition model 10,24 . Collectively, these observations support a model in 4 which the gene architecture (e.g., size of introns) and gene nucleotide composition bias (e.g., GC or 5 AT content) influence local processes at the exon level, such as nucleosome positioning and intron 6 removal. As exon recognition also depends on the binding to the pre-mRNAs of splicing factors that 7 interact with compositionally-biased sequences, one interesting possibility is that the nature of these 8 splicing factors depends at least in part on the gene nucleotide composition bias. In this setting, we 9 have recently reported that exons regulated by different splicing factors have different nucleotide 10 composition bias 25 . 11Here, we have investigated the relationship between the splicing process, gene nucleotide 12 composition bias and chromatin organization at both the local and global levels. We initially 13 identified sets of exons activated by different splicing factors and then demonstrated that analysing 14 the nucleotide composition bias provided a better understanding of the interplay between chromatin 15 organization and splicing-related features, which collectively affect exon recognition. We propose 16 that nucleotide composition bias not only contributes to the 1D and 3D genome organization, but 17 has also local consequences at the exon level during the splicing process. 18 19 20 Results 21Splicing factor-dependent GC-rich and AT-rich ex...

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Interplay between coding and exonic splicing regulatory sequences

Cited by 2 publications

References 47 publications

TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

Interplay between gene nucleotide composition bias and splicing

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