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In brief: November 2009Transcription Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation In this study, Zippo et al. reveal a mechanism by which phosphorylation of histone 3 (H3) triggers a cascade that activates stalled RNA polymerase II and leads to transcriptional elongation. They observed that phosphorylation at Ser10 of H3 (pre-acetylated at Lys9; H3K9acS10pho) at the serum-inducible FOS-like antigen 1 (FOSL1) enhancer leads to acetylation of H4 at Lys16 (H4K16ac). This modification is mediated by the recruitment of 14-3-3 proteins following phosphorylation of H3K9ac, which in turn recruit the acetyltransferase MOF (also known as MYST1) to H4K16. This histone code (H3K9acS10pho–H4K16ac) is preferentially recognized by bromodomain-containing protein 4 (BRD4), which associates with positive transcription elongation factor b (P-TEFb), ultimately leading to activation of RNA polymerase II and transcription elongation. Molecular motors Kinesin-8 motors act cooperatively to mediate length-dependent microtubule depolymerization Kinesin 8 family members are motor proteins that depolymerize microtubules and control cell length, but the mechanism by which they achieve this was not fully understood. Varga et al. observed that the yeast kinesin 8 Kip3 bound to microtubule filaments and moved processively towards the plus ends. The presence of other Kip3 molecules reduced the plus end residence time of individual Kip3 molecules, and this correlated with increased depolymerization by the removal of one tubulin dimer for each dissociated Kip3. Interestingly, Kip3 paused on the microtubule plus ends until another Kip3 molecule attached, leading to dissociation of the original Kip3. They propose that depolymerization is achieved either by removal of a tubulin dimer when Kip3 reaches the plus end or through the dissociation of Kip3–tubulin when a second Kip3 binds the microtubule. Innate immunity Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice This study helps to explain the increased susceptibility to certain bacterial infections of patients with type I haemochromatosis, who have a mutation in the haemochromatosis gene, HFE, resulting in dysregulated iron homeostasis; this could affect both the host immune response and microbial growth, but the precise mechanisms of disease have been unclear. HFE-deficient mice have decreased production of tumour necrosis factor and interleukin-6 by macrophages in response to Salmonella typhimurium or lipopolysaccharide. This was shown to be a result of low concentrations of intracellular iron in peritoneal macrophages, which specifically inhibited Toll-like receptor 4 signalling through the adaptor proteins TRAM and TRIF but not through MYD88 and MAL (also known as TIRAP). Deliberately lowering iron levels in macrophages using small-molecule inhibitors of the HFE pathway decreased the severity of intestinal inflammation induced by various means, which potentially offers a new anti-inflammatory strategy. Apoptosis Membrane-bound Fas ligand only is essential for Fas-induced apoptosis The induction of T cell apoptosis by FAS ligand (FASL; also known as TNFSF6) through its receptor FAS (also known as TNFRSF6) is required for the termination of chronic immune responses, and mice and humans with mutations in the genes encoding FAS or FASL develop lymphadenopathy and autoimmunity. FASL is expressed as both membrane-bound and secreted forms but the relative contribution of these two forms to apoptosis was not known. O'Reilly et al. show that membrane-bound but not secreted FASL triggers target cell killing and activation-induced cell death of T cells, which is necessary to prevent splenomegaly, lymphadenopathy, hypergammaglobulinaemia and autoantibody accumulation. By contrast, mice that expressed only secreted FASL succumbed to glomerulonephritis and histiocytic sarcoma. So, membrane-bound FASL is essential for cell killing and protects against autoimmunity, whereas high levels of secreted FASL promote autoimmunity and tumorigenesis through non-apoptotic functions. Senescence SnoN functions as a tumour suppressor by inducing premature senescence SNO-N, which is related to the oncoprotein SKI, can have pro-oncogenic functions owing to its capacity to repress transforming growth factor- Ageing A transcription elongation factor that links signals from the reproductive system to lifespan extension in Caenorhabditis elegans This paper provides insights into the mechanism responsible for the link between reproduction and longevity by showing that the transcription elongation factor TCER-1 is required for the increase in lifespan conferred by the loss of the germ line in Caenorhabditis elegans. The removal of germ cells leads to increased levels of TCER-1 in the soma. This promotes the expression of a subset of genes that are regulated by the transcription factor forkhead box protein O (FOXO), which is important in lifespan extension. Neurodegenerative disease Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease Parkin mutations are linked to autosomal recessive juvenile Parkinson's disease (AR-JP). Parkin has ubiquitin ligase activity; however, there is also evidence that it can act as a transcriptional regulator. Here the authors show that parkin binds to and transactivates the p53 promoter to repress p53 transcription and that mutations associated with familial AR-JP abolish this activity. These findings indicate a new function for parkin, the disruption of which may contribute to AR-JP. Ion channels An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action TASK-3 channels are acid-sensitive 'background' K+ channels that are activated by some anaesthetics. Pang et al. show that deletion of TASK-3 channels reduced sensitivity to halothane in mice and, unexpectedly, abolished a particular frequency (type II theta) of synchronized cortical oscillatory activity. Furthermore, the animals demonstrated abnormal sleep patterns. These findings suggest a link between TASK-3 channels' role in the generation of type II theta oscillations and the regulation of sleep behaviour. Obesity and diabetes The protein kinase IKK These studies showed that a high-fat diet increased nuclear factor Memory Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation Selective activation of muscarinic acetylcholine receptors (mAChRs) that are involved in memory — such as the M1 mAChR — could improve cognitive function in Alzheimer's disease. This paper describes benzyl quinolone carboxylic acid (BQCA), a selective allosteric potentiator of the M1 mAChR that reduced the concentration of acetylcholine required to activate the receptor by more than 100-fold. BQCA reversed memory deficits in a mouse model of contextual fear conditioning and increased wakefulness. | |
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