3 research outputs found
Towards understanding the genetics of Autism
Autism spectrum disorder (ASD) includes a group of neurodevelopmental disorders that affect communication skills, social interaction and intellectual ability. Despite evidence suggesting a strong genetic link with ASD, the genetic determinant remains unclear. Early studies focusing on candidate genes have shown that several genes associated with neuronal synaptic function are involved in development of ASD. Linkage studies have identified several single nucleotide polymorphisms (SNPs) associated with ASD, and genome-wide association studies have implicated several loci, but failed to recognize a single specific locus with strong significance, indicating heterogeneity in ASD genetic determinants. Detection of de novo copy number variations and single nucleotide variants in several ASD probands has confirmed the genetic heterogeneity of the disease. More interestingly, next generation sequencing approaches have recently identified novel candidate genes and several point mutations in sporadic ASDs, thus increasing our knowledge of ASD etiology. The current review summarizes the findings of recent studies using genetic and genomic approaches to understand the underlying molecular mechanisms of ASD.Scopu
Role of Protein Arginine Methyltransferase 5 (PRMT5) in WNT/β--CATENIN proliferative signaling in breast cancer
Protein arginine methyltransferase 5 (PRMT5) activity is dysregulated in many aggressive
cancers and its enhanced levels are associated with increased tumor growth and survival.
In this study, we show that PRMT5 is overexpressed in breast cancer cell lines, and that it
promotes WNT/B-CATENIN proliferative signaling through epigenetic silencing of
pathway antagonists, DKK1 and DKK3, by binding to their promoter and inducing
symmetric dimethylation of H3R8 and H4R3, leading to enhanced expression of c-MYC,
CYCLIN D1 and SURVIVIN. Our findings also show that PRMT5 inhibition using
compound 5 (CMP5), reduces PRMT5 recruitment and PRMT5-induced epigenetic marks
in the promoter regions of DKK1 and DKK3, which consequently results in reduced
expression of CYCLIN D1 and SURVIVIN. Furthermore, CMP5 treatment either alone or
in combination with 5-Azacytidine and Trichostatin A restored expression of DKK1 and
DKK3 in TNBCs. In addition, PRMT5 inhibition in TNBCs inhibited AKT/mTOR
signaling by reducing phosphorylation of AKT and mTOR at Ser473 and Ser2448,
respectively. These molecular changes were associated with reduced proliferation,
migration and invasion of breast cancer cells, and induced their death
Sphingolipids in Childhood Asthma and Obesity (SOAP Study): A Protocol of a Cross-Sectional Study
Asthma and obesity are two of the most common chronic conditions in children and adolescents. There is increasing evidence that sphingolipid metabolism is altered in childhood asthma and is linked to airway hyperreactivity. Dysregulated sphingolipid metabolism is also reported in obesity. However, the functional link between sphingolipid metabolism, asthma, and obesity is not completely understood. This paper describes the protocol of an ongoing study on sphingolipids that aims to examine the pathophysiology of sphingolipids in childhood asthma and obesity. In addition, this study aims to explore the novel biomarkers through a comprehensive multi-omics approach including genomics, genome-wide DNA methylation, RNA-Seq, microRNA (miRNA) profiling, lipidomics, metabolomics, and cytokine profiling. This is a cross-sectional study aiming to recruit 440 children from different groups: children with asthma and normal weight (n = 100), asthma with overweight or obesity (n = 100), overweight or obesity (n = 100), normal weight (n = 70), and siblings of asthmatic children with normal weight, overweight, or obesity (n = 70). These participants will be recruited from the pediatric pulmonology, pediatric endocrinology, and general pediatric outpatient clinics at Sidra Medicine, Doha, Qatar. Information will be obtained from self-reported questionnaires on asthma, quality of life, food frequency (FFQ), and a 3-day food diary that are completed by the children and their parents. Clinical measurements will include anthropometry, blood pressure, biochemistry, bioelectrical impedance, and pulmonary function tests. Blood samples will be obtained for sphingolipid analysis, serine palmitoyltransferase (SPT) assay, whole-genome sequencing (WGS), genome-wide DNA methylation study, RNA-Seq, miRNA profiling, metabolomics, lipidomics, and cytokine analysis. Group comparisons of continuous outcome variables will be carried out by a one-way analysis of variance or the Kruskal–Wallis test using an appropriate pairwise multiple comparison test. The chi-squared test or a Fisher’s exact test will be used to test the associations between categorical variables. Finally, multivariate analysis will be carried out to integrate the clinical data with multi-omics data. This study will help us to understand the role of dysregulated sphingolipid metabolism in obesity and asthma. In addition, the multi-omics data from the study will help to identify novel genetic and epigenetic signatures, inflammatory markers, and mechanistic pathways that link asthma and obesity in children. Furthermore, the integration of clinical and multi-omics data will help us to uncover the potential interactions between these diseases and to offer a new paradigm for the treatment of pediatric obesity-associated asthma