cell

无水印完整版本下载：www.n-ebook.com Doc uCo m P DF Tria l ww w.pd fwiz ard. com Leading Edge In This Issue De Novo Mutations at Hots PAGE 1431 Michaelson et al. carry out whole-genome sequencing of monozygotic twins with autism spectrum disorders (ASD) and their parents and find that mutation rates vary by up correlated with particular intrinsic characteri genes involved in ASD and other diseases. genetic variation and disease risk. Wnt Caught Smuggling Hip PAGE 1443 and PAGE 1457 Wnt signaling stabilizes the transcriptional coactivator b-catenin, which forms a complex with TCF4 to regulate target genes. PAGE 1474 bidirectionally at promoters. Using an efficient enzymatic method, CapSeq, for 5’-anchored Pol II transcription profiling, Gu PAGE 1528 Mitochondrial respiratory chain complexes are assembled from proteins translated in the cytoplasm and in the mitochondria. Luga et al. provide new insight into how stromal cells in the tumormicroenviron-D F i . iz m PAGE 1417 A genome-wide analysis byMellen et al. of 5hmC, 5mC, and gene expression in neuronal subtypes in vivo reveals an enrichment of 5hmC in active genes. They further show thatMeCP2 protein recognizes and binds 5hmCand 5mCand that a mutation in MeCP2 that causes Rett syndrome preferentially inhibits 5hmC binding. ment can stimulate primary tumors into metastatic behavior. The authors show that Wnt11-containing exosomes secreted by fibroblasts act on neighboring breast cancer cells to activate the planar cell polarity pathway, promoting motility and invasive behavior. Rett’s-Related Reader for 5hmC Mick et al. show that themitochondrial inner membrane translocase subunit TIM21 ushers cytoplasmically translated compo- nents of electron transport chain complexes (ETCs) away from the translocase and promotes their integration into ETC complex assembly intermediates that also contain mitochondrially translated subunits. Message in a Bottle for Tumor Cells PAGE 1542 ocuwww et al. identify Pol II transcription start sites in Caenorhabditis elegans. Interestingly, they show that csRNAs expressed at promoters genome-wide are the precursors for Piwi-interacting RNAs (piRNAs), nearly doubling the number of piRNAs avail- able to promote silencing of foreign nucleic acid sequences. Usher for Electron Transport Chain AssemblyCompdfw Ligase IV is a key factor in double-strand break (DSB) repair via nonhomologous end-joining (NHEJ). Srivastava et al. identify a small molecule inhibitor of Ligase IV that promotes the accumulation of DSBs to trigger cell death. This is shown to impede tumor progression in mice and improve the efficacy of DSB-inducing agents used for chemotherapy. Piwi, If the Cap Fits. PAGE 1488 RNA polymerase II (Pol II) produces 18–40 nt capped small RNAs (csRNAs) of mysterious function that are often expressed PDard.co Now, the transcriptional coactivators TAZ and YAP1 are identified as effectors of Wnt signaling, independent of their estab- lished roles in Hippo signaling. Azzolin et al. show that TAZ stabilization, as part of a complex with b-catenin, is a key feature of Wnt signaling. Rosenbluh et al. identify an alternative transcriptional complex composed of YAP1, b-catenin, and TBX5 that is essential for the proliferation and tumorigenicity of b-catenin-driven cancer cell lines. Double-Strand Breakthrough Tr 无水印完 to 100-fold throughout the genome. The identifiedmutational hotspots that are stics of the DNA sequence and chromatin structure and are characteristic of The findings implicate hypermutability as a significant factor shaping human po Parts al pots Cell 151, December 21, 2012 ª2012 Elsevier Inc. 1391 整版本下载：www.n-ebook.com es s nucleate at the preautophago- ral model of the PAS in which red for PAS formation. The cres- and tethers highly curved vesi- chromatin remodelers during the dif Refractory Cells Get w PAGE 1617 The generation of iPSCs is extreme blasts in different stages of the rep them molecularly. The authors iden to generate iPSCs from the refracto Focal Adhesions Show PAGE 1513 Cells can sense differences in the s stiffer areas during normal developm tasis. Plotnikov et al. show that cel test—the local stiffness of the micro stiffer areas. They identify pharmaco vate or inactivate tugging, which ma ological states. 无水 Do . Foxa2 collaborates with H2A.Z to target nucleosomes for removal by ATP-dependentferentiation process to foster gene expression.ith the Reprogramly inefficient, complicating mechanistic dissection of the process. Polo et al. sort fibro- rogramming process, including those refractory to reprogramming, and characterize tify genes that enhance reprogramming and are able ry population. Their Stiff Upper Lip tiffness of their microenvironment and move towards ent and wound healing and also during cancer metas- ww cles, suggesting a mechanism for initiating autophagosomal biogenesis. Encouraging a Clingy Receptor to Play the Field PAGE 1557 HLA-DM catalyzes the binding of microbial peptides to HLA-DR, the MHC class II cell- surface receptor, which subsequently presents antigen to T cells. Crystal structures of the HLA-DM-HLA-DR complex presented by Pos et al. reveal how DM changes the conformation of DR to allow it to rapidly sample peptides and only form lasting interactions with those of very high affinity. Speeding to Steady State PAGE 1569 Signaling circuits often face a fundamental tradeoff between accelerating their response speed while maintaining final levels of an output protein below a cytotoxic threshold. Teng et al. characterize an accelerator circuit that speeds the rate of gene expression without amplifying steady-state expression levels. This circuit operates in the human herpes virus cytomegalo- virus where it confers a replicative fitness advantage for infected cells. Converging on Synapse Elimination in Autism PAGE 1581 Elimination of excitatory synapses is a critical process for experience-dependent refinement of neuronal circuits during brain development, learning, and memory. Tsai et al. provide evidence for a functional convergence for multiple autism-linked genes in synapse elimination through the ubiquitination and degradation of the postsynaptic scaffolding protein PSD-95. T2D Risk—Liver Gets a New Look PAGE 1595 Single-nucleotide polymorphisms in TCF7L2 (encoding the Wnt effector TCF4) are the strongest genetic risk factors for type 2 diabetes. Most studies on TCF7L2 have focused on b cells. However Boj et al. now show that genetically removing TCF4 from bcells inmicehasnoeffect,whereasmanipulatingTCF4 levels in liver inducesmajorchanges inmetabolism.Afterbirthandduring fasting, Wnt/TCF4 directly activates a metabolic gene program in liver, suggesting a new perspective for the human risk alleles. Setting the Nucleosomal Stage for Differentiation PAGE 1608 Li et al. demonstrate that dynamic, genome-wide repositioning of nucleosomes accompanies the differentiation of embryonic stem cells into prehepatic endodermcuC om PDF Tria l w.pd fwiz ard. com Crescent Rolls Up Autophagosom PAGE 1501 Duringmacroautophagy, a phagophore forms as vesicle somal structure (PAS). Ragusa et al. present a structu dimerization of the Atg17-Atg31-Atg29 complex is requi cent-shaped dimers assemble with Atg1, which binds to ls use focal adhesions to tug repeatedly at—and thus environment in order to guide cell movement towards logical and genetic perturbations that selectively acti- y enable control of cell movement in normal and path- Cell 151, December 21, 2012 ª2012 Elsevier Inc. 1393 印完整版本下载：www.n-ebook.com Leading Edge tance stemic insulin resistance. Recent mune cell populations to modu- ociated insulin resistance. d Breast Milk Have in uman breast milk express immunomodu- e glucose tolerance and insulin sensitivity. oni, parasite eggs trapped in host tissues in attenuated immune responses by the ). Bhargava et al. (2012) demonstrate that lycan lacto-N-fucopentaose III (LNFPIII), that is secreted from a saline-soluble homogenate of helmith eggs or human breast authors show that LNFPIII has beneficial hepatosteatosis. LNFPIII affects de novo master lipogenic transcription factor SRE is partly driven by the upregulation of the axis. Collectively, LNFPIII treatment shifts of its therapeutic potential. Bhargava et al. (2012). Nat. Med. 18, 1665 The Secret Life of Secret Neutrophils, which comprise about 90% adipose of mice fed a HFD. This begs the initiating the inflammatory cascade seen periments, Talukdar et al. (2012) show tha of inflammation-induced insulin resistanc secreted by neutrophils, plays a crucial m elastase expression and activity increase in itant to HFD-induced neutrophil infiltration improves glucose intolerance, whereas treatment with recombinant elastaseDoc uC Tria l w that this actionby secretedelastasepossibly results in recruitment andpolarization of adipose macrophages (M1) and also, as part of a feed-forward secondary mechanism, additional neutrophil accumulation. Thus, the secret life of secreted elastase is revealed, and neutrophils can be added to the list of immune cells Neutrofil elastase is a mediator of the low- grade inflammation seen in insulin resis- tance. Image courtesy of Dayoung Oh. mediating the low-grade inflammation seen in insulin resistance driven by obesity. Talukdar et al. (2012). Nat. Med. 18, 1407–1412. has the opposite effect. Moreover, genetic deletion of elastase in mice results in substantially higher glucose tolerance and lower fasting insulin concentration in both liver and adipose tissue, as highlighted by increased levels of insulin receptor substrate 1 (IRS1) (an interesting twist based on the ability of extracellular neutro- phil elastase to gain access to the intracellular space andmediate its degradation) and AKT phosphorylation. The authors next show that the proinflammatory effects of elastase are dependent on TLR-4 signaling and NFkB activation and suggest 无水印完 is Il-10 dependent, the glycan also has critical Il-10-independent functions. The effects in liver because it can protect against diet-induced lipid accumulation and lipogenesis by reducing expression of hepatic lipogenic enzymes, including the BP-1C. These effects are Il-10 independent, and the LNFPIII-mediated reduction negative SREBP-1C regulator and nuclear receptor FXRa via an ERK-AP1-FXRa the immune profile to an anti-inflammatory state, which warrants further exploration –1672. ed Elastase of granulocytes, are enriched in the question, do neutrophils play a role in in obesity? In a series of elegant ex- t neutrophils contribute to the etiology e and that elastase, a serine protease echanistic role in the process. Indeed, the adipose and liver ofmice, concom- , and chemical inhibition of the enzyme om ww .pdf wiza r milk is effective in reducing the chronic inflammation seen in diabetes induced by a high-fat diet (HFD), thus resulting in improved metabolic function. Specifically, LNFPIII increases interleukin-10 (Il-10), a cytokine that has been shown to improve metabolic homeostasis. Mice treated with LNFPIII have less proinflammatory M1 and more anti-inflammatory M2 macrophage-specific gene expression in white adipose tissue (WAT), resulting in enhanced insulin signaling, reduced WAT inflammation, and improved systemic glucose homeostasis. An interesting observation is that although the immunomodulatory activity of LNFPIII in WAT Photograph of adult schistosomes from the CDC DPDx image library. Image courtesy of Donald. A. Harn PDFd.com Select The Many Faces of Insulin Resis Low-grade inflammation in the liver and adipose tissue drives sy reports, discussed in this Select, identify new pathways used by im late chronic metabolic inflammation that results from obesity-ass What Do Helmiths an Common? Parasitic worms such as helmiths and h latory glycans recently shown to improv During infection with Schistosoma mans initiate a cascade of events that results host (hence prolonged parasite survival the LewisX trisaccharide, part of the g Cell 151, December 21, 2012 ª2012 Elsevier Inc. 1395 整版本下载：www.n-ebook.com Multipurpose Natural Killer T Cells In the management of obesity-induced insulin resistance, adapting proven therapies for other disorders would be highly desirable. A report by Lynch et al. (2012) suggests just such an approach. They identify an innate T lympho- cyte population of invariant natural killer T (iNKT) cells that are protective against the development of HFD-driven insulin resistance. iNKT cells are enriched in the activate TLR-4 has remained elusive. The paper by Pal et al. (2012) addresses this conundrum and suggests that fetuin is involves not only the presence of FFAs, fetuin on TLR-4 are crucial for fetuin binding, and F fetuin is the candidate site for TLR-4 binding to TLR-4 and represents a new therapeutic t Pal et al. (2012). Nat. Med. 18, 1279–1285. Iphigenia Tzameli Editor, Trends in Endocrinology and Meta 无水印完 Doc u ww z osphorylation requires intact fetuin, and the lipotoxicity-driven insulin resistance , and TLR-4 but also their physical interaction. Indeed, two leucine-rich repeats FAs induce insulin resistance, whereas the terminal b-galactosidase moiety of . Thus, fetuin acts as an adaptor protein and endogenous presenter of FFAs arget in the management lipid-induced insulin resistance. bolism w the mysterious ligand. This is intriguing because fetuin, a liver secretory glycoprotein and major carrier of FFAs in the circulation, has already been labeled as a marker of low-grade metabolic inflammation because it stimulates production of cytokines and chemokines from adipocytes and macrophages. The authors show that fetuin fits the role of a TLR-4 ligand because it can recapitulate many of the effects seen previously that linked TLR-4 action to insulin resistance. For example, mice with fetuin and TLR-4 knockdown or hepatectomized rats (another means for reducing fetuin expression) are protected from HFD-induced insulin resistance and NFkB activation. Restoring fetuin expression in the knockdown mouse model results in lipid-induced insulin resistance, whereas infusion of the proinflammatory lipid palmitate, a FFA with maximum binding to fetuin but not to TLR-4, fails to activate TLR-4 in mice with fetuin knockdown. The authors show that FFA-mediated activation of TLR-4 and subsequent NFkB ph Com.pdfwi fat depots of lean humans, get depleted in obesity, and reappear after bariatric surgery. Similarly, in the mouse, iNKT are severely depleted in the leptin- deficient (ob/ob) mouse model, progressively decline to markedly reduced numbers during HFD feeding, and bounce back when the mice are switched to a chow diet. The authors show that this unique immune repertoire of fat- derived iNKT cells produces more anti-inflammatory IL-10 after stimulation with the prototypical lipid antigen alpha-galactosylceramide (aGC), which is intriguing because IL-10 promotes a phenotype switch toward the M2 anti- inflammatory macrophage population. Compelling data from mice with iNKT cell deficiency show a correlation with increased metabolic syndrome and insulin resistance that worsens on a HFD and increased M1 macrophage infiltration in the adipose. Interestingly, adoptive transfer of iNKT cells to obese mice not only improves glucose homeostasis but also triggers significant fat loss. The next burning question of course is, what is the effect of aGC on the insulin-resistance profile of these mouse models? Indeed, aGC injection causes a significant decrease in adipose mass and cell size, improves glucose homeostasis, and results in markedly increased iNKT cell numbers. As aGC is already used as a treatment in multiple cancer settings, and it does not cause hypoglycemia in the diabetic and euglycemic murine models, it is a matter of time before its effect on humans with insulin resistance is determined. Lynch et al. (2012). Immunity 37, 574–587. Finding the Mysterious TLR-4 Ligand Free fatty acids (FFAs) mediate activation of the TLR-4/NFkB pathway to promote insulin resistance. However, how FFAs Dual energy X-ray absorptiometry scan shows that iNKT-deficient mice have significantly more body fat than wild-type mice, but lean mass is unchanged. Image courtesy of Linda Lynch. PD F Tr ial ard. com Cell 151, December 21, 2012 ª2012 Elsevier Inc. 1397 整版本下载：www.n-ebook.com Leading Edge t o it .u m u st d c . structure. the small scale (<100 bp) in three sequence is G+C and CpG-rich. Genesc r (Conrad et al., 2011; Campbell et al., 2012; Kong et al., 2012; Sun et al., 2012). Michaelson et al. (2012) then quences. In great part, this is explained by the high mutability of the CpG dinucle- otide and, to a lesser extent, of the coding sequence that has been better conserved, either within or between species, was predicted to be modestly show that the majority of these DNA changes were of paternal origin. This is CpNpG trinucleotide arising mostly from the spontaneous deamination of 5mC (up to 70%) more prone to mutation. This implies that deleterious variants are to an average human genome-widemuta- tion rate of 1 3 10�8 per base pair per generation, similar to previous estimates regions between embryonic stem cells and male germ cells. By far the greatest enrichment is that for trinucleotide se- their mutations being repaired less effi- ciently in germline cells. Somewhat counterintuitively, protein- The authors deep-sequenced immor- talized lymphoblastoid cell line genomes from ten pairs of monozygotic twins with autism and from their parents. On average, 58 DNA changes were present in both twins, yet were absent from their parents, and thus were likely to have arisen de novo in their common germline genome, rather than being somatic or cell linemutations. This number translates sequence classes: simple repeats, DNase 1 hypersensitivity sites from embryonic stem cells, and various trinucleotide sequences. The known high rate of repli- cation slippage in simple repeats likely accounts for the first enrichment. The high mutation rate in DNase 1 hypersensi- tivity sites is, however, unexpected (Pre- ndergast et al., 2007) but could reflect substantial differences in open chromatin associated with recessive or dominant disease were predicted to show even greater tendencies for being mutated, at approximately 35% and 40% average increases, respectively, results that are in agreement with a previous cross- species comparison (Huang et al., 2004). These findings imply that features of such disease genes make them slightly more susceptible to being mutated or to Do ww Previews Loaded Dice for Chris P. Ponting1,* 1MRC Functional Genomics Unit, Departmen Oxford OX1 3PT, UK *Correspondence: chris.ponting@dpag.ox.ac http://dx.doi.org/10.1016/j.cell.2012.12.002 Not all bases in the human geno that individuals can acquire clu single base pair change differs a The replication or maintenance of human genomes through cell lineages or across generations is not always completely faithful. Rare mutations accumulate whose eventual fate is to be lost through drift or negative selection or to be fixed in our future population. Although these mutations are random, in the sense that when or where they occur is highly unpre- dictable, not all base pairs stand an even chance of being mutated, and conse- quently, there are regions of the human genome that are hotspots, or coldspots, of change. Pinpointing these hotspots might lead to a better understanding of both mutational mechanisms and the frequency by which spontaneous se- quence change causes noninherited genetic disease. In this issue of Cell, Michaelson et al. (2012) identify de novo germline mutations in monozygotic twins who are concordant for autism and propose that mutational variation is largely explained by intrinsic characteris- tics of DNA s