Schizophrenia (SZ) is a complex disease characterized by impaired neuronal functioning. Although defective alternative splicing has been linked to SZ, the molecular mechanisms responsible are ...unknown. Additionally, there is limited understanding of the early transcriptomic responses to neuronal activation. Here, we profile these transcriptomic responses and show that long non-coding RNAs (lncRNAs) are dynamically regulated by neuronal activation, including acute downregulation of the lncRNA Gomafu, previously implicated in brain and retinal development. Moreover, we demonstrate that Gomafu binds directly to the splicing factors QKI and SRSF1 (serine/arginine-rich splicing factor 1) and dysregulation of Gomafu leads to alternative splicing patterns that resemble those observed in SZ for the archetypal SZ-associated genes DISC1 and ERBB4. Finally, we show that Gomafu is downregulated in post-mortem cortical gray matter from the superior temporal gyrus in SZ. These results functionally link activity-regulated lncRNAs and alternative splicing in neuronal function and suggest that their dysregulation may contribute to neurological disorders.
MicroRNAs (miRNAs) represent an important class of small regulatory RNAs that control gene expression posttranscriptionally by targeting mRNAs for degradation or translation inhibition. Early studies ...have revealed a complex role for miRNAs in major biological processes such as development, differentiation, growth and metabolism. MiR-137 in particular, has been of great interest due to its critical role in brain function and putative involvement in the etiology of both neuropsychiatric disorders and cancer. Several lines of evidence suggest that development, differentiation and maturation of the nervous system is strongly linked to the expression of miR-137 and its regulation of a large number of downstream target genes in various pathways. Dysregulation of this molecule has also been implicated in major mental illnesses through its position in a variant allele highly associated with schizophrenia in the largest mega genome-wide association studies. Interestingly, miR-137 has also been shown to act as a tumor suppressor, with numerous studies finding reduced expression in neoplasia including brain tumor. Restoration of miR-137 expression has also been shown to inhibit cell proliferation, migration and metastasis, and induce cell cycle arrest, differentiation and apoptosis. These properties of miR-137 propose its potential for prognosis, diagnosis and as a therapeutic target for treatment of several human neurological and neoplastic disorders. In this review, we provide details on the discovery, targets, function, regulation and disease involvement of miR-137 with a broad look at recent discovery in this area.
Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate ...the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs; N=294), comprising 47.6% of the sample who were impaired across all cognitive measures, and a cognitively spared group (CS; N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function.
The availability of high density panels of molecular markers has prompted the adoption of genomic selection (GS) methods in animal and plant breeding. In GS, parametric, semi-parametric and ...non-parametric regressions models are used for predicting quantitative traits. This article shows how to use neural networks with radial basis functions (RBFs) for prediction with dense molecular markers. We illustrate the use of the linear Bayesian LASSO regression model and of two non-linear regression models, reproducing kernel Hilbert spaces (RKHS) regression and radial basis function neural networks (RBFNN) on simulated data and real maize lines genotyped with 55,000 markers and evaluated for several trait–environment combinations. The empirical results of this study indicated that the three models showed similar overall prediction accuracy, with a slight and consistent superiority of RKHS and RBFNN over the additive Bayesian LASSO model. Results from the simulated data indicate that RKHS and RBFNN models captured epistatic effects; however, adding non-signal (redundant) predictors (interaction between markers) can adversely affect the predictive accuracy of the non-linear regression models.
Circular RNAs (circRNAs) are covalently closed structural isoforms of linear mRNA which have been observed across a broad range of species and tissues. Here, we provide a comprehensive circRNAs ...expression catalogue for the rat including 8 organs of both sexes during 4 developmental stages using a public RNAseq dataset. These analyses revealed thousands of circular RNA species, many expressed in an organ-specific manner along with their host genes which were enriched with tissue-specific biological functions. A large number of circRNAs also displayed a developmental-dependent expression pattern and are accumulated during ageing. CircRNAs also displayed some sexually dimorphic expression, with gender associated differences observed in various tissues and developmental stages. These observations suggest that circRNAs are dynamically expressed in a spatial-, temporal- and gender-specific manner in mammals, and may have important biological function in differentiation, development and aging.
ABSTRACT
We present SCUBA-2 850 $\mathrm{ \mu}$m observations of 13 candidate starbursting protoclusters selected using Planck and Herschel data. The cumulative number counts of the 850 $\mathrm{ ...\mu}$m sources in 9 of 13 of these candidate protoclusters show significant overdensities compared to the field, with the probability <10−2 assuming the sources are randomly distributed in the sky. Using the 250, 350, 500, and 850 $\mathrm{ \mu}$m flux densities, we estimate the photometric redshifts of individual SCUBA-2 sources by fitting spectral energy distribution templates with an MCMC method. The photometric redshift distribution, peaking at 2 < z < 3, is consistent with that of known z > 2 protoclusters and the peak of the cosmic star formation rate density (SFRD). We find that the 850 $\mathrm{ \mu}$m sources in our candidate protoclusters have infrared luminosities of $L_{\mathrm{IR}}\gtrsim 10^{12}\, \mathrm{L}_{\odot }$ and star formation rates of SFR = (500–1500) M⊙ yr−1. By comparing with results in the literature considering only Herschel photometry, we conclude that our 13 candidate protoclusters can be categorized into four groups: six of them being high-redshift starbursting protoclusters, one being a lower redshift cluster or protocluster, three being protoclusters that contain lensed dusty star-forming galaxies or are rich in 850 $\mathrm{ \mu}$m sources, and three regions without significant Herschel or SCUBA-2 source overdensities. The total SFRs of the candidate protoclusters are found to be comparable or higher than those of known protoclusters, suggesting our sample contains some of the most extreme protocluster population. We infer that cross-matching Planck and Herschel data is a robust method for selecting candidate protoclusters with overdensities of 850 $\mathrm{ \mu}$m sources.
MicroRNA expression profiling and quantitative reverse transcription-PCR analysis of the superior temporal gyrus and the dorsolateral prefrontal cortex revealed a significant schizophrenia-associated ...increase in global microRNA expression. This change was associated with an elevation of primary microRNA processing and corresponded with an increase in the microprocessor component DGCR8. The biological implications for this extensive increase in gene silencing are profound, and were exemplified by members of the miR-15 family and other related microRNA, which were significantly upregulated in both brain regions. This functionally convergent influence is overrepresented in pathways involved in synaptic plasticity and includes many genes and pathways associated with schizophrenia, some of which were substantiated in vitro by reporter gene assay. Given the magnitude of microRNA changes and their wide sphere of influence, this phenomenon could represent an important dimension in the pathogenesis of schizophrenia.
Synovial sarcomas are aggressive soft-tissue malignancies that express chromosomal translocation-generated fusion genes, SS18-SSX1 or SS18-SSX2 in most cases. Here, we report a mouse sarcoma model ...expressing SS18-SSX1, complementing our prior model expressing SS18-SSX2. Exome sequencing identified no recurrent secondary mutations in tumors of either genotype. Most of the few mutations identified in single tumors were present in genes that were minimally or not expressed in any of the tumors. Chromosome 6, either entirely or around the fusion gene expression locus, demonstrated a copy number gain in a majority of tumors of both genotypes. Thus, by fusion oncogene coding sequence alone, SS18-SSX1 and SS18-SSX2 can each drive comparable synovial sarcomagenesis, independent from other genetic drivers. SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences overall. In direct tumorigenesis comparisons, SS18-SSX2 was slightly more sarcomagenic than SS18-SSX1, but equivalent in its generation of biphasic histologic features. Meta-analysis of human synovial sarcoma patient series identified two tumor-gentoype-phenotype correlations that were not modeled by the mice, namely a scarcity of male hosts and biphasic histologic features among SS18-SSX2 tumors. Re-analysis of human SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences, but highlighted increased native SSX2 expression in SS18-SSX1 tumors. This suggests that the translocated locus may drive genotype-phenotype differences more than the coding sequence of the fusion gene created. Two possible roles for native SSX2 in synovial sarcomagenesis are explored. Thus, even specific partial failures of mouse genetic modeling can be instructive to human tumor biology.
Summary
Numerous health consequences of tobacco smoke exposure have been characterized, and the effects of smoking on traditional measures of male fertility are well described. However, a growing ...body of data indicates that pre‐conception paternal smoking also confers increased risk for a number of morbidities on offspring. The mechanism for this increased risk has not been elucidated, but it is likely mediated, at least in part, through epigenetic modifications transmitted through spermatozoa. In this study, we investigated the impact of cigarette smoke exposure on sperm DNA methylation patterns in 78 men who smoke and 78 never‐smokers using the Infinium Human Methylation 450 beadchip. We investigated two models of DNA methylation alterations: (i) consistently altered methylation at specific CpGs or within specific genomic regions and (ii) stochastic DNA methylation alterations manifest as increased variability in genome‐wide methylation patterns in men who smoke. We identified 141 significantly differentially methylated CpGs associated with smoking. In addition, we identified a trend toward increased variance in methylation patterns genome‐wide in sperm DNA from men who smoke compared with never‐smokers. These findings of widespread DNA methylation alterations are consistent with the broad range of offspring heath disparities associated with pre‐conception paternal smoke exposure and warrant further investigation to identify the specific mechanism by which sperm DNA methylation perturbation confers risk to offspring health and whether these changes can be transmitted to offspring and transgenerationally.
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