The CUGBP2 Splicing Factor Regulates an Ensemble of Branchpoints from Perimeter Binding Sites with Implications for Autoregulation

Alternative pre-mRNA splicing adjusts the transcriptional output of the genome by generating related mRNAs from a single primary transcript, thereby expanding protein diversity. A fundamental unanswered question is how splicing factors achieve specificity in the selection of target substrates despite the recognition of information-poor sequence motifs. The CUGBP2 splicing regulator plays a key role in the brain region-specific silencing of the NI exon of the NMDA R1 receptor. However, the sequence motifs utilized by this factor for specific target exon selection and its role in splicing silencing are not understood. Here, we use chemical modification footprinting to map the contact sites of CUGBP2 to GU-rich motifs closely positioned at the boundaries of the branch sites of the NI exon, and we demonstrate a mechanistic role for this specific arrangement of motifs for the regulation of branchpoint formation. General support for a branch site-perimeter–binding model is indicated by the identification of a group of novel target exons with a similar configuration of motifs that are silenced by CUGBP2. These results reveal an autoregulatory role for CUGBP2 as indicated by its direct interaction with functionally significant RNA motifs surrounding the branch sites upstream of exon 6 of the CUGBP2 transcript itself. The perimeter-binding model explains how CUGBP2 can effectively embrace the branch site region to achieve the specificity needed for the selection of exon targets and the fine-tuning of alternative splicing patterns

Food patterns and components of the metabolic syndrome in men and women: a cross-sectional study within the Malmo Diet and Cancer cohort

This study examined the relations between food patterns and five components of the metabolic syndrome in a sample of Swedish men (n = 2,040) and women (n = 2,959) aged 45-68 years who joined the Malmo Diet and Cancer study from November 1991 to February 1994. Baseline examinations included an interview-administered diet history, a self-administered questionnaire, blood pressure and anthropologic measurements, and blood samples donated after an overnight fast. Cluster analysis identified six food patterns for which 43 food group variables were used. Logistic regression analysis was used to examine the risk of each component (hyperinsulinemia, hyperglycemia, hypertension, dyslipidemia, and central obesity) and food patterns, controlling for potential confounders. The study demonstrated relations, independent of specific nutrients, between food patterns and hyperglycemia and central obesity in men and hyperinsulinemia in women. Food patterns dominated by fiber bread provided favorable effects, while food patterns high in refined bread or in cheese, cake, and alcoholic beverages contributed adverse effects. In women, food patterns dominated by milk-fat-based spread showed protective relations with hyperinsulinemia. Relations between risk factors and food patterns may partly depend on gender differences in metabolism or food consumption and on variations in confounders across food patterns