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Abstract Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide polymorphisms (SNPs) with functional implications for the microRNA’s expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.

A major determinant of fruit production in longan (Dimocarpus longan Lour.) is the difficulty of blossoming. In this study, high-throughput microRNA sequencing (miRNA-Seq) was carried out to compare differentially expressed miRNAs (DEmiRNAs) and their target genes between a continuous flowering cultivar ‘Sijimi’ (SJ), and a unique cultivar ‘Lidongben’ (LD), which blossoms only once in the season. Over the course of our study, 1662 known miRNAs and 235 novel miRNAs were identified and 13,334 genes were predicted to be the target of 1868 miRNAs. One conserved miRNA and 29 new novel miRNAs were identified as differently expressed; among them, 16 were upregulated and 14 were downregulated. Through the KEGG pathway and cluster analysis of DEmiRNA target genes, three critical regulatory pathways, plant–pathogen interaction, plant hormone signal transduction, and photosynthesis-antenna protein, were discovered to be strongly associated with the continuous flowering trait of the SJ. The integrated correlation analysis of DEmiRNAs and their target mRNAs revealed fourteen important flowering-related genes, including COP1-like, Casein kinase II, and TCP20. These fourteen flowering-related genes were targeted by five miRNAs, which were novel-miR137, novel-miR76, novel-miR101, novel-miR37, and csi-miR3954, suggesting these miRNAs might play vital regulatory roles in flower regulation in longan. Furthermore, novel-miR137 was cloned based on small RNA sequencing data analysis. The pSAK277-miR137 transgenic Arabidopsis plants showed delayed flowering phenotypes. This study provides new insight into molecular regulation mechanisms of longan flowering.

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.

We examined the influence of the genome-wide significant schizophrenia risk variant rs1625579 near the microRNA (miRNA)-137 ( MIR137 ) gene on well-established sources of phenotypic variability in schizophrenia: age-at-onset of psychosis and brain structure. We found that the MIR137 risk genotype strongly predicts an earlier age-at-onset of psychosis across four independently collected samples of patients with schizophrenia ( n =510; F 1,506 =17.7, P =3.1 × 10 −5 ). In an imaging-genetics subsample that included additional matched controls ( n =213), patients with schizophrenia who had the MIR137 risk genotype had reduced white matter integrity ( F 3,209 =13.6, P =3.88 × 10 −8 ) throughout the brain as well as smaller hippocampi and larger lateral ventricles; the brain structure of patients who were carriers of the protective allele was no different from healthy control subjects on these neuroimaging measures. Our findings suggest that MIR137 substantially influences variation in phenotypes that are thought to have an important role in clinical outcome and treatment response. Finally, the possible consequences of genetic risk factors may be distinct in patients with schizophrenia compared with healthy controls.

BackgroundMicroRNAs (miRNAs) are non-coding gene transcripts involved in post-transcriptional regulation of genes. Recent studies identified miRNAs as important regulators of learning and memory in model organisms. So far, no mutations in specific miRNA genes have been associated with impaired cognitive functions.Methods and resultsIn three sibs and two unrelated patients with intellectual disability (ID), overlapping 1p21.3 deletions were detected by genome-wide array analysis. The shortest region of overlap included dihydropyrimidine dehydrogenase (DPYD) and microRNA 137 (MIR137). DPYD is involved in autosomal recessive dihydropyrimidine dehydrogenase deficiency. Hemizygous DPYD deletions were previously suggested to contribute to a phenotype with autism spectrum disorder and speech delay. Interestingly, the mature microRNA transcript microRNA-137 (miR-137) was recently shown to be involved in modulating neurogenesis in adult murine neuronal stem cells. Therefore, this study investigated the possible involvement of MIR137 in the 1p21.3-deletion phenotype. The patients displayed a significantly decreased expression of both precursor and mature miR-137 levels, as well as significantly increased expression of the validated downstream targets microphthalmia-associated transcription factor (MITF) and Enhancer of Zeste, Drosophila, Homologue 2 (EZH2), and the newly identified target Kruppel-like factor 4 (KLF4). The study also demonstrated significant enrichment of miR-137 at the synapses of cortical and hippocampal neurons, suggesting a role of miR-137 in regulating local synaptic protein synthesis machinery.ConclusionsThis study showed that dosage effects of MIR137 are associated with 1p21.3 microdeletions and may therefore contribute to the ID phenotype in patients with deletions harbouring this miRNA. A local effect at the synapse might be responsible.

A recent 'mega-analysis' combining genome-wide association study data from over 40,000 individuals identified novel genetic loci associated with schizophrenia (SCZ) at genome-wide significance level. The strongest finding was a locus within an intron of a putative primary transcript for microRNA MIR137. In the current study, we examine the impact of variation at this locus (rs1625579, G/T; where T is the common and presumed risk allele) on brain activation during a sentence completion task that differentiates individuals with SCZ, bipolar disorder (BD), and their relatives from controls. We examined three groups of individuals performing a sentence completion paradigm: (i) individuals at high genetic risk of SCZ (n=44), (ii) individuals at high genetic risk of BD (n=90), and (iii) healthy controls (n=81) in order to test the hypothesis that genotype at rs1625579 would influence brain activation. Genotype groups were assigned as 'RISK-' for GT and GG individuals, and 'RISK+' for TT homozygotes. The main effect of genotype was significantly greater activation in the RISK- individuals in the posterior right medial frontal gyrus, BA 6. There was also a significant genotype(*)group interaction in the left amygdala and left pre/postcentral gyrus. This was due to differences between the controls (where individuals with the RISK- genotype showed greater activation than RISK+ subjects) and the SCZ high-risk group, where the opposite genotype effect was seen. These results suggest that the newly identified SCZ locus may influence brain activation in a manner that is partly dependent on the presence of existing genetic susceptibility for SCZ.

MIR137 is implicated in brain development and encodes a microRNA that regulates neuronal maturation and adult neurogenesis. Recently, a common genetic variant within MIR137 showed genome wide evidence of association with schizophrenia, and with altered amygdala activation in those at genetic risk for schizophrenia. Following this evidence, we investigated the effects of MIR137 genotype on neuronal activity during face processing. By grouping 81 healthy participants as carrier or non-carriers of the MIR137 rs1625579 risk allele associated with schizophrenia, we investigated MIR137's effects on altered cortical response during an fMRI face processing task and altered functional connectivity using the amygdala as a seed region. Homozygous carriers of the risk allele were observed to show relatively increased functional connectivity between the right amygdala and frontal regions that play a key role in emotion processing and regulation (e.g. the cingulate and prefrontal cortex). Our findings provide the first evidence that the rs1625579 variant affects fronto-amygdala functional connectivity, providing further evidence that MIR137 may contribute to forms of psychosis in which affective symptoms are more prominent. •We examined MIR137 rs1625579 effects on brain function in controls using fMRI.•Brain activation/connectivity was examined during a face processing task.•rs1625579 risk homozygotes showed increased fronto-amygdala functional connectivity.•This study provides the first evidence that MIR137 affects functional connectivity.

Mismatch Repair (MMR) gene dysregulation plays a fundamental role in Lynch Syndrome (LS) pathogenesis, a form of hereditary colorectal cancer. Loss or overexpression of key MMR genes leads to genome instability and tumorigenesis; however, the mechanisms controlling MMR gene expression are unknown. One such gene, MSH2, exerts an important role, not only in MMR, but also in cell proliferation, apoptosis, and cell cycle control. In this study, we explored the functions and underlying molecular mechanisms of increased MSH2 expression related to a c.*226A>G variant in the 3′untranslated (UTR) region of MSH2 that had been previously identified in a subject clinically suspected of LS. Bioinformatics identified a putative binding site for miR-137 in this region. To verify miRNA targeting specificity, we performed luciferase gene reporter assays using a MSH2 3′UTR psiCHECK-2 vector in human SW480 cells over-expressing miR-137, which showed a drastic reduction in luciferase activity (p > 0.0001). This effect was abolished by site-directed mutagenesis of the putative miR-137 seed site. Moreover, in these cells we observed that miR-137 levels were inversely correlated with MSH2 expression levels. These results were confirmed by results in normal and tumoral tissues from the patient carrying the 3′UTR c.*226A>G variant in MSH2. Finally, miR-137 overexpression in SW480 cells significantly suppressed cell proliferation in a time- and dose-dependent manner (p < 0.0001), supporting a role for MSH2 in apoptosis and cell proliferation processes. Our findings suggest miR-137 helps control MSH2 expression via its 3′UTR and that dysregulation of this mechanism appears to promote tumorigenesis in colon cells.

Background Previous studies indicated that lncRNA taurine upregulated gene 1 (TUG1) played essential roles in human cancers. This study aimed to investigate its function in infantile hemangioma (IH). Methods A total of 30 pairs of clinical infantile specimens were used in this study. The expression of TUG1 in IH tissues was assessed by quantitative reverse transcriptase PCR (qRT-PCR). Two short hairpin RNA targeting TUG1 (sh-TUG1-1 and sh-TUG1-2) were transfected into hemangioma-derived endothelial cells, HemECs, to block its expression. The effects of TUG1 on HemECs were evaluated by Cell Counting Kit-8 (CCK-8), colony formation assay, wound healing assay, and Transwell assay. The underlying molecular mechanism of TUG1 was investigated by Starbase prediction and luciferase reporter assay and further determined by loss- and gain-of-function approaches. In addition, the role of TUG1 on tumorigenesis of HemECs was confirmed in an in vivo mouse model. Results TUG1 was significantly upregulated in infant hemangioma tissues compared with normal adjacent subcutaneous tissues. The loss- and gain-of-function approaches indicated that TUG1 overexpression promoted proliferation, migration, and invasion of HemECs in vitro, and TUG1 knockdown inhibited the tumorigenesis of HemECs in vivo. Specifically, TUG1 could compete with IGFBP5 for miR137 binding. Rescue experiments further confirmed the role of the TUG1/miR137/IGFBP5 axis in HemECs. Conclusion TUG1 was closely associated with the progression of IH by regulating the miR-137/IGFBP5 axis, which might be a potential target for IH treatment.

Obesity is a highly heritable but genetically heterogeneous disorder. Various well-known microdeletion syndromes (e.g. 1p36, 2q37, 6q16, 9q34, 17p11.2) can cause this phenotype along with intellectual disability (ID) and other findings. Chromosomal microarrays have identified ‘new' microdeletion/duplication syndromes often associated with obesity. We report on 2 unrelated patients with an overlapping region of deletion at 1p21.3p21.2, and a third patient with a de novo recurrent unbalanced translocation der(8)t(8;12)(p23.1;p13.31), detected by 180K array CGH in a prospective cohort of syndromic obesity patients. Deletion of 1p21.3 is a rare condition, and there have been only 11 cases of the same recurrent translocation between chromosomes 8 and 12 [t(8;12)] reported to date. The former has been associated with ID, autistic spectrum disorder (ASD) and mild dysmorphic features, and in 4 patients who were obese or had a tendency to obesity, a minimal overlapping region of 2 genes, DPYD and MIR137, was detected; t(8;12) has recently been recognized to cause a childhood obesity syndrome due to duplication of the GNB3 gene. Thus, our findings add to the existing literature on the clinical description of these new syndromes, providing additional support that these loci are associated with syndromic obesity. We suggest that heterozygous loss of MIR137 may contribute to obesity as well as ID and ASD.