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Pancreatic β‐cells are critical mediators of glucose homeostasis in the body, and proper cellular nutrient metabolism is critical to β‐cell function. Several interacting signaling networks that uniquely control β‐cell metabolism produce essential substrates and co‐factors for catalytic reactions, including reactions that modify chromatin. Chromatin modifications, in turn, regulate gene expression. The reactions that modify chromatin are therefore well‐positioned to adjust gene expression programs according to nutrient availability. It follows that dysregulation of nutrient metabolism in β‐cells may impact chromatin state and gene expression through altering the availability of these substrates and co‐factors. Metabolic disorders such as type 2 diabetes (T2D) can significantly alter metabolite levels in cells. This suggests that a driver of β‐cell dysfunction during T2D may be the altered availability of substrates or co‐factors necessary to maintain β‐cell chromatin state. Induced changes in the β‐cell chromatin modifications may then lead to dysregulation of gene expression, in turn contributing to the downward cascade of events that leads to the loss of functional β‐cell mass, and loss of glucose homeostasis, that occurs in T2D. [ABSTRACT FROM AUTHOR]

We describe a model-based method, PING, for predicting nucleosome positions in MNase-Seq and MNase- or sonicated- ChIP-Seq data. PING compares favorably to NPS and TemplateFilter in scalability, accuracy and robustness to low read density. To demonstrate that PING predictions from widely available sonicated data can have sufficient spatial resolution to be to be useful for biological inference, we use Illumina H3K4me1 ChIP-seq data to detect changes in nucleosome positioning around transcription factor binding sites due to tamoxifen stimulation, to discriminate functional and nonfunctional transcription factor binding sites more effectively than with enrichment profiles, and to confirm that the pioneer transcription factor Foxa2 associates with the accessible major groove of nucleosomal DNA. [ABSTRACT FROM AUTHOR]

Molecular mechanisms responsible for lymphoma resistance to apoptosis often involve the bcl-2 pathway. In this study, we investigated the cell signaling pathways activated in bcl-2-overexpressing human mantle cell lymphoma cell lines (JVM-2 and Z-138) that have been treated with oblimersen, a molecular gene silencing strategy that effectively suppresses bcl-2 in vitro and in vivo. Z-138 cells expressed higher levels of bcl-2 and were more sensitive to the effects of bcl-2 silencing, mediated by oblimersen or bcl-2 small interfering RNA, in vitro. Tumors derived following injection of Z-138 cells were sensitive to oblimersen as judged by decreases in tumor growth rate and decreases in cell proliferation (as measured by Ki-67). Immunohistochemistry and Western blot analysis of oblimersen-treated Z-138 tumors revealed a dose-dependent decrease in bcl-2 levels and an associated increase in the proapoptotic proteins caspase-3 and caspase-9. Silencing bcl-2 in Z-138 xenografts revealed an associated dose-dependent suppression of bax, a decrease in nuclear factor-kappaB and phospho-nuclear factor-kappaB, and transient loss of p53 levels. Coimmunoprecipitation studies suggest that the latter observation is mediated by an association between bcl-2 and phospho-mdm2. Bcl-2 silencing also led to p27 down-regulation and coimmunoprecipitation studies point to a role for bcl-2 in regulation of p27 localization/degradation. Bcl-2 silencing was also correlated with loss of cyclin D1a protein levels but not cyclin D1b levels. Coimmunoprecipitation studies indicate that bcl-2 may mediate its effects on cyclin D1a via interaction with p38 mitogen-activated protein kinase as well as a previously unreported interaction between bcl-2 and cyclin D1a.