The Arabidopsis lncRNA ASCO modulates the transcriptome through interaction with splicing factors.

Alternative splicing (AS) is a major source of transcriptome diversity. Long noncoding RNAs (lncRNAs) have emerged as regulators of AS through different molecular mechanisms. In Arabidopsis thaliana, the AS regulators NSRs interact with the ALTERNATIVE SPLICING COMPETITOR (ASCO) lncRNA. Here, we analyze the effect of the knock-down and overexpression of ASCO at the genome-wide level and find a large number of deregulated and differentially spliced genes related to flagellin responses and biotic stress. In agreement, ASCO-silenced plants are more sensitive to flagellin. However, only a minor subset of deregulated genes overlaps with the AS defects of the nsra/b double mutant, suggesting an alternative way of action for ASCO. Using biotin-labeled oligonucleotides for RNA-mediated ribonucleoprotein purification, we show that ASCO binds to the highly conserved spliceosome component PRP8a. ASCO overaccumulation impairs the recognition of specific flagellin-related transcripts by PRP8a. We further show that ASCO also binds to another spliceosome component, SmD1b, indicating that it interacts with multiple splicing factors. Hence, lncRNAs may integrate a dynamic network including spliceosome core proteins, to modulate transcriptome reprogramming in eukaryotes.

Network Analysis of Metabolite GWAS Hits: Implication of CPS1 and the Urea Cycle in Weight Maintenance.

BACKGROUND AND SCOPE: Weight loss success is dependent on the ability to refrain from regaining the lost weight in time. This feature was shown to be largely variable among individuals, and these differences, with their underlying molecular processes, are diverse and not completely elucidated. Altered plasma metabolites concentration could partly explain weight loss maintenance mechanisms. In the present work, a systems biology approach has been applied to investigate the potential mechanisms involved in weight loss maintenance within the Diogenes weight-loss intervention study. METHODS AND RESULTS: A genome wide association study identified SNPs associated with plasma glycine levels within the CPS1 (Carbamoyl-Phosphate Synthase 1) gene (rs10206976, p-value = 4.709e-11 and rs12613336, p-value = 1.368e-08). Furthermore, gene expression in the adipose tissue showed that CPS1 expression levels were associated with successful weight maintenance and with several SNPs within CPS1 (cis-eQTL). In order to contextualize these results, a gene-metabolite interaction network of CPS1 and glycine has been built and analyzed, showing functional enrichment in genes involved in lipid metabolism and one carbon pool by folate pathways. CONCLUSIONS: CPS1 is the rate-limiting enzyme for the urea cycle, catalyzing carbamoyl phosphate from ammonia and bicarbonate in the mitochondria. Glycine and CPS1 are connected through the one-carbon pool by the folate pathway and the urea cycle. Furthermore, glycine could be linked to metabolic health and insulin sensitivity through the betaine osmolyte. These considerations, and the results from the present study, highlight a possible role of CPS1 and related pathways in weight loss maintenance, suggesting that it might be partly genetically determined in humans.

Dual function of MIPS1 as a metabolic enzyme and transcriptional regulator.

Because regulation of its activity is instrumental either to support cell proliferation and growth or to promote cell death, the universal myo-inositol phosphate synthase (MIPS), responsible for myo-inositol biosynthesis, is a critical enzyme of primary metabolism. Surprisingly, we found this enzyme to be imported in the nucleus and to interact with the histone methyltransferases ATXR5 and ATXR6, raising the question of whether MIPS1 has a function in transcriptional regulation. Here, we demonstrate that MIPS1 binds directly to its promoter to stimulate its own expression by locally inhibiting the spreading of ATXR5/6-dependent heterochromatin marks coming from a transposable element. Furthermore, on activation of pathogen response, MIPS1 expression is reduced epigenetically, providing evidence for a complex regulatory mechanism acting at the transcriptional level. Thus, in plants, MIPS1 appears to have evolved as a protein that connects cellular metabolism, pathogen response and chromatin remodeling.

Gene duplication within the Green Lineage: the case of TEL genes.

Recent years have witnessed a breathtaking increase in the availability of genome sequence data, providing evidence of the highly duplicate nature of eukaryotic genomes. Plants are exceptional among eukaryotic organisms in that duplicate loci compose a large fraction of their genomes, partly because of the frequent occurrence of polyploidy (or whole-genome duplication) events. Tandem gene duplication and transposition have also contributed to the large number of duplicated genes in plant genomes. Evolutionary analyses allowed the dynamics of duplicate gene evolution to be studied and several models were proposed. It seems that, over time, many duplicated genes were lost and some of those that were retained gained new functions and/or expression patterns (neofunctionalization) or subdivided their functions and/or expression patterns between them (subfunctionalization). Recent studies have provided examples of genes that originated by duplication with successive diversification within plants. In this review, we focused on the TEL (TERMINAL EAR1-like) genes to illustrate such mechanisms. Emerged from the mei2 gene family, these TEL genes are likely to be land plant-specific. Phylogenetic analyses revealed one or two TEL copies per diploid genome. TEL gene degeneration and loss in several Angiosperm species such as in poplar and maize seem to have occurred. In Arabidopsis thaliana, whose genome experienced at least three polyploidy events followed by massive gene loss and genomic reorganization, two TEL genes were retained and two new shorter TEL-like (MCT) genes emerged. Molecular and expression analyses suggest for these genes sub- and neofunctionalization events, but confirmation will come from their functional characterization.

Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis.

Spondyloarthritis (SpA) is a chronic inflammatory disorder with a strong genetic predisposition dominated by the role of HLA-B27. However, the contribution of other genes to the disease susceptibility has been clearly demonstrated. We previously reported significant evidence of linkage of SpA to chromosome 9q31-34. The current study aimed to characterize this locus, named SPA2. First, we performed a fine linkage mapping of SPA2 (24 cM) with 28 microsatellite markers in 149 multiplex families, which allowed us to reduce the area of investigation to an 18 cM (13 Mb) locus delimited by the markers D9S279 and D9S112. Second, we constructed a linkage disequilibrium (LD) map of this region with 1,536 tag single-nucleotide polymorphisms (SNPs) in 136 families (263 patients). The association was assessed using a transmission disequilibrium test. One tag SNP, rs4979459, yielded a significant P-value (4.9 x 10(-5)). Third, we performed an extension association study with rs4979459 and 30 surrounding SNPs in LD with it, in 287 families (668 patients), and in a sample of 139 cases and 163 controls. Strong association was observed in both familial and case/control datasets for several SNPs. In the replication study, carried with 8 SNPs in an independent sample of 232 cases and 149 controls, one SNP, rs6478105, yielded a nominal P-value<3 x 10(-2). Pooled case/control study (371 cases and 312 controls) as well as combined analysis of extension and replication data showed very significant association (P<5 x 10(-4)) for 6 of the 8 latter markers (rs7849556, rs10817669, rs10759734, rs6478105, rs10982396, and rs10733612). Finally, haplotype association investigations identified a strongly associated haplotype (P<8.8 x 10(-5)) consisting of these 6 SNPs and located in the direct vicinity of the TNFSF15 gene. In conclusion, we have identified within the SPA2 locus a haplotype strongly associated with predisposition to SpA which is located near to TNFSF15, one of the major candidate genes in this region.