Occupancy Classification of Position Weight Matrix-Inferred Transcription Factor Binding Sites

BACKGROUND: Computational prediction of Transcription Factor Binding Sites (TFBS) from sequence data alone is difficult and error-prone. Machine learning techniques utilizing additional environmental information about a predicted binding site (such as distances from the site to particular chromatin features) to determine its occupancy/functionality class show promise as methods to achieve more accurate prediction of true TFBS in silico. We evaluate the Bayesian Network (BN) and Support Vector Machine (SVM) machine learning techniques on four distinct TFBS data sets and analyze their performance. We describe the features that are most useful for classification and contrast and compare these feature sets between the factors. RESULTS: Our results demonstrate good performance of classifiers both on TFBS for transcription factors used for initial training and for TFBS for other factors in cross-classification experiments. We find that distances to chromatin modifications (specifically, histone modification islands) as well as distances between such modifications to be effective predictors of TFBS occupancy, though the impact of individual predictors is largely TF specific. In our experiments, Bayesian network classifiers outperform SVM classifiers. CONCLUSIONS: Our results demonstrate good performance of machine learning techniques on the problem of occupancy classification, and demonstrate that effective classification can be achieved using distances to chromatin features. We additionally demonstrate that cross-classification of TFBS is possible, suggesting the possibility of constructing a generalizable occupancy classifier capable of handling TFBS for many different transcription factors

Dietary fruits and vegetables and cardiovascular diseases risk

Diet is likely to be an important determinant of cardiovascular disease (CVD) risk. In this article, we will review the evidence linking the consumption of fruit and vegetables and CVD risk. The initial evidence that fruit and vegetable consumption has a protective effect against CVD came from observational studies. However, uncertainty remains about the magnitude of the benefit of fruit and vegetable intake on the occurrence of CVD and whether the optimal intake is five portions or greater. Results from randomized controlled trials do not show conclusively that fruit and vegetable intake protects against CVD, in part because the dietary interventions have been of limited intensity to enable optimal analysis of their putative effects. The protective mechanisms of fruit and vegetables may not only include some of the known bioactive nutrient effects dependent on their antioxidant, anti-inflammatory, and electrolyte properties, but also include their functional properties, such as low glycemic load and energy density. Taken together, the totality of the evidence accumulated so far does appear to support the notion that increased intake of fruits and vegetables may reduce cardiovascular risk. It is clear that fruit and vegetables should be eaten as part of a balanced diet, as a source of vitamins, fiber, minerals, and phytochemicals. The evidence now suggests that a complicated set of several nutrients may interact with genetic factors to influence CVD risk. Therefore, it may be more important to focus on whole foods and dietary patterns rather than individual nutrients to successfully impact on CVD risk reduction. A clearer understanding of the relationship between fruit and vegetable intake and cardiovascular risk would provide health professionals with significant information in terms of public health and clinical practice

Blimp1 Activation by AP-1 in Human Lung Cancer Cells Promotes a Migratory Phenotype and Is Inhibited by the Lysyl Oxidase Propeptide

B lymphocyte-induced maturation protein 1 (Blimp1) is a master regulator of B cell differentiation, and controls migration of primordial germ cells. Recently we observed aberrant Blimp1 expression in breast cancer cells resulting from an NF-κB RelB to Ras signaling pathway. In order to address the question of whether the unexpected expression of Blimp1 is seen in other epithelial-derived tumors, we selected lung cancers as they are frequently driven by Ras signaling. Blimp1 was detected in all five lung cancer cell lines examined and shown to promote lung cancer cell migration and invasion. Interrogation of microarray datasets demonstrated elevated BLIMP1 RNA expression in lung adenocarcinoma, pancreatic ductal carcinomas, head and neck tumors as well as in glioblastomas. Involvement of Ras and its downstream kinase c-Raf was confirmed using mutant and siRNA strategies. We next addressed the issue of mechanism of Blimp1 activation in lung cancer. Using knockdown and ectopic expression, the role of the Activator Protein (AP)-1 family of transcription factors was demonstrated. Further, chromatin immunoprecipitation assays confirmed binding to identified AP-1 elements in the BLIMP1 promoter of ectopically expressed c-Jun and of endogenous AP-1 subunits following serum stimulation. The propeptide domain of lysyl oxidase (LOX-PP) was identified as a tumor suppressor, with ability to reduce Ras signaling in lung cancer cells. LOX-PP reduced expression of Blimp1 by binding to c-Raf and inhibiting activation of AP-1, thereby attenuating the migratory phenotype of lung cancer cells. Thus, Blimp1 is a mediator of Ras/Raf/AP-1 signaling that promotes cell migration, and is repressed by LOX-PP in lung cancer

Control of Bone Mass and Remodeling by PTH Receptor Signaling in Osteocytes

Osteocytes, former osteoblasts buried within bone, are thought to orchestrate skeletal adaptation to mechanical stimuli. However, it remains unknown whether hormones control skeletal homeostasis through actions on osteocytes. Parathyroid hormone (PTH) stimulates bone remodeling and may cause bone loss or bone gain depending on the balance between bone resorption and formation. Herein, we demonstrate that transgenic mice expressing a constitutively active PTH receptor exclusively in osteocytes exhibit increased bone mass and bone remodeling, as well as reduced expression of the osteocyte-derived Wnt antagonist sclerostin, increased Wnt signaling, increased osteoclast and osteoblast number, and decreased osteoblast apoptosis. Deletion of the Wnt co-receptor LDL related receptor 5 (LRP5) attenuates the high bone mass phenotype but not the increase in bone remodeling induced by the transgene. These findings demonstrate that PTH receptor signaling in osteocytes increases bone mass and the rate of bone remodeling through LRP5-dependent and -independent mechanisms, respectively

Long non-coding RNAs and cancer: a new frontier of translational research?

Author manuscriptTiling array and novel sequencing technologies have made available the transcription profile of the entire human genome. However, the extent of transcription and the function of genetic elements that occur outside of protein-coding genes, particularly those involved in disease, are still a matter of debate. In this review, we focus on long non-coding RNAs (lncRNAs) that are involved in cancer. We define lncRNAs and present a cancer-oriented list of lncRNAs, list some tools (for example, public databases) that classify lncRNAs or that scan genome spans of interest to find whether known lncRNAs reside there, and describe some of the functions of lncRNAs and the possible genetic mechanisms that underlie lncRNA expression changes in cancer, as well as current and potential future applications of lncRNA research in the treatment of cancer.RS is supported as a fellow of the TALENTS Programme (7th R&D Framework Programme, Specific Programme: PEOPLE—Marie Curie Actions—COFUND). MIA is supported as a PhD fellow of the FCT (Fundação para a Ciência e Tecnologia), Portugal. GAC is supported as a fellow by The University of Texas MD Anderson Cancer Center Research Trust, as a research scholar by The University of Texas System Regents, and by the Chronic Lymphocytic Leukemia Global Research Foundation. Work in GAC’s laboratory is supported in part by the NIH/ NCI (CA135444); a Department of Defense Breast Cancer Idea Award; Developmental Research Awards from the Breast Cancer, Ovarian Cancer, Brain Cancer, Multiple Myeloma and Leukemia Specialized Programs of Research Excellence (SPORE) grants from the National Institutes of Health; a 2009 Seena Magowitz–Pancreatic Cancer Action Network AACR Pilot Grant; the Laura and John Arnold Foundation and the RGK Foundation

Solution structure of the interacting domains of the Mad-Sin3 complex: implications for recruitment of a chromatin-modifying complex.

Gene-specific targeting of the Sin3 corepressor complex by DNA-bound repressors is an important mechanism of gene silencing in eukaryotes. The Sin3 corepressor specifically associates with a diverse group of transcriptional repressors, including members of the Mad family, that play crucial roles in development. The NMR structure of the complex formed by the PAH2 domain of mammalian Sin3A with the transrepression domain (SID) of human Mad1 reveals that both domains undergo mutual folding transitions upon complex formation generating an unusual left-handed four-helix bundle structure and an amphipathic alpha helix, respectively. The SID helix is wedged within a deep hydrophobic pocket defined by two PAH2 helices. Structure-function analyses of the Mad-Sin3 complex provide a basis for understanding the underlying mechanism(s) that lead to gene silencing