Stochastic Activation of Enhancers in the Innate Immune Response by the Histone Demethylase JMJD2D

The architecture of chromatin is complex and plays a substantial role in all of the biological processes involving DNA. In particular, transcriptional activation depends on the interplay of dozens of chromatin modifiers to establish an epigenetic landscape permissive of gene transcription. Among the most dynamic histone modifications are the acetylation and methylation at histone 3 lysine 9, but the precise roles of their modifiers in conserved transcriptional programs remain unknown. Using the poly I:C-induced transcriptional response in MEFs as our model, we find that JMJD2d is a positive regulator of type I interferon responses. siRNA-depletion of the H3K9 demethylase JMJD2d attenuates gene activation and overexpression of JMJD2d potentiates the IFN response. We find that the underlying mechanism involves the activation of enhancers – knockdown of JMJD2d attenuates stimulus-induced enhancer activation, which is normally characterized by the accumulation of acetylated H3K9 and increased enhancer RNA transcription. In short, JMJD2d appears to control IFN responses by enabling the transition of enhancers from ‘poised’ (H3K9me3) to ‘active’ (H3K9ac) that allows for eRNA production. In support of this hypothesis, we observe that JMJD2d is tightly associated with enhancers in the genome and preferentially binds active enhancer regions. Taken together, JMJD2d represents the first example of a chromatin modifier with enhancer specificity and emerges as a potential therapeutic target in the modulation of IFN responses

The Roles of Individual Mammalian Argonautes in RNA Interference In Vivo

Argonaute 2 (Ago2) is the only mammalian Ago protein capable of mRNA cleavage. It has been reported that the activity of the short interfering RNA targeting coding sequence (CDS), but not 3′ untranslated region (3′UTR) of an mRNA, is solely dependent on Ago2 in vitro. These studies utilized extremely high doses of siRNAs and overexpressed Ago proteins, as well as were directed at various highly expressed reporter transgenes. Here we report the effect of Ago2 in vivo on targeted knockdown of several endogenous genes by siRNAs, targeting both CDS and 3′UTR. We show that siRNAs targeting CDS lose their activity in the absence of Ago2, whereas both Ago1 and Ago3 proteins contribute to residual 3′UTR-targeted siRNA-mediated knockdown observed in the absence of Ago2 in mouse liver. Our results provide mechanistic insight into two components mediating RNAi under physiological conditions: mRNA cleavage dependent and independent. In addition our results contribute a novel consideration for designing most efficacious siRNA molecules with the preference given to 3′UTR targeting as to harness the activity of several Ago proteins.Alnylam Pharmaceuticals (Firm

Изучение жизнеспособности культуры Escherichia coli в присутствии солей лития

Effective antiviral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. We describe an epigenetic mechanism that determines cell type–specific differences in IFN and IFN-stimulated gene (ISG) expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and ISG correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity

Cystic Neoplasms of the Pancreas

Cystic neoplasms of the pancreas are being identified at an increasing frequency largely due to the increased use of abdominal cross-sectional imaging. These neoplasms represent a heterogeneous group of tumors with various genetic alterations, molecular features, and risks of malignancy. Despite the use of high-resolution radiographic studies, endoscopic evaluation, cyst fluid analysis, and novel molecular diagnostics, many of these lesions remain difficult to classify without operative resection. These diagnostic challenges are coupled with an improving but limited understanding of the natural history of these neoplasms. Treatment of pancreatic cystic neoplasms therefore remains controversial but consists largely of a selective tumor-specific approach to surgical resection. Future research remains necessary to better discriminate the biological behavior of these tumors in order to more appropriately select patients for operative intervention. </jats:p