Thursday, September 29, 2011

Hot off the presses! Sep 30 Cell

The Sep 30 issue of the Cell is now up on Pubget (About Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • In This Issue
    - Cell 147(1):1,3 (2011)
  • Cancer's Epigenome
    - Cell 147(1):5,7 (2011)
    Large-scale cancer genomics projects are just starting to trickle into the literature, and the flow will only grow in size and impact in the upcoming year. Nevertheless, the studies so far are already reshaping our view of tumor progression, especially in terms of how cancer manipulates the epigenome for fast growth and adaptability. This Select discusses recent genomics articles that, collectively, offer a new mechanism for cancer evolution and highlight the rising importance of chromatin remodeling factors in cancer.
  • Human Genome: What's Been Most Surprising?
    - Cell 147(1):9-10 (2011)
  • Genomics in Africa: Avoiding Past Pitfalls
    - Cell 147(1):11-13 (2011)
    A landmark genomics project is taking shape in Africa that shifts the power and prominence to local scientists. If successful, the program will offer valuable insights into the inheritance of common diseases and reshape the paradigm of foreign-funded research.
  • Genomics Reaches the Clinic: From Basic Discoveries to Clinical Impact
    - Cell 147(1):14-16 (2011)
    Today, more than ever, basic science research provides significant opportunities to advance our understanding about the genetic basis of human disease. Close interactions among laboratory, computational, and clinical research communities will be crucial to ensure that genomic discoveries advance medical science and, ultimately, improve human health.
  • Genetics and Genomics to the Clinic: A Long Road ahead
    - Cell 147(1):17-19 (2011)
    Advances in genomic technology have produced an explosion of new information about the genetic basis for human disease, fueling extraordinarily high expectations for improved treatments. This perspective will take brief stock of what genetics/genomics have brought to clinical practice to date and what we might expect for the future.
  • Translocation Mapping Exposes the Risky Lifestyle of B Cells
    - Cell 147(1):20-22 (2011)
    Recurrent chromosomal translocations can drive oncogenesis, but how they form has remained elusive. Now, and characterize the genome-wide spectrum of translocations that form from a single double-stranded break, revealing that specific loci have an intrinsic predisposition for frequent chromosomal rearrangements.
  • Splicing up Pluripotency
    - Cell 147(1):22-24 (2011)
    In this issue of Cell, identify a new splice variant of FOXP1 that directly regulates the expression of pluripotency genes. It endows human embryonic stem cells with their pluripotent nature and is required for the reprogramming of somatic cells to induced pluripotent stem cells.
  • Unweaving the Autism Spectrum
    - Cell 147(1):24-25 (2011)
    Although genes associated with human autism spectrum disorders have been identified, bridging the gap between genetics and the patchwork of behavioral deficits associated with the disease remains an enormous challenge. now show that mice lacking CNTNAP2, a gene that causes a rare form of epilepsy associated with autistic features and language impairment, display similar phenotypes to their human counterparts, raising hopes that such models may speed the identification of neuronal circuitries underlying the core features of autism.
  • A Blueprint for Advancing Genetics-Based Cancer Therapy
    - Cell 147(1):26-31 (2011)
    In the era of next-generation sequencing, there are significant challenges to harnessing cancer genome information to develop novel therapies. Key research thrusts in both academia and industry will speed this transition, and lessons learned for cancer will more broadly shape the process for genetic contributions to the therapy of disease more broadly.
  • Clan Genomics and the Complex Architecture of Human Disease
    - Cell 147(1):32-43 (2011)
    Human diseases are caused by alleles that encompass the full range of variant types, from single-nucleotide changes to copy-number variants, and these variations span a broad frequency spectrum, from the very rare to the common. The picture emerging from analysis of whole-genome sequences, the 1000 Genomes Project pilot studies, and targeted genomic sequencing derived from very large sample sizes reveals an abundance of rare and private variants. One implication of this realization is that recent mutation may have a greater influence on disease susceptibility or protection than is conferred by variations that arose in distant ancestors.
  • Metagenomics and Personalized Medicine
    - Cell 147(1):44-56 (2011)
    The microbiome is a complex community of Bacteria, Archaea, Eukarya, and viruses that infect humans and live in our tissues. It contributes the majority of genetic information to our metagenome and, consequently, influences our resistance and susceptibility to diseases, especially common inflammatory diseases, such as type 1 diabetes, ulcerative colitis, and Crohn's disease. Here we discuss how host-gene-microbial interactions are major determinants for the development of these multifactorial chronic disorders and, thus, for the relationship between genotype and phenotype. We also explore how genome-wide association studies (GWAS) on autoimmune and inflammatory diseases are uncovering mechanism-based subtypes for these disorders. Applying these emerging concepts will permit a more complete understanding of the etiologies of complex diseases and underpin the development of both next-generation animal models and new therapeutic strategies for targeting personalized disea! se phenotypes.
  • Mapping Rare and Common Causal Alleles for Complex Human Diseases
    - Cell 147(1):57-69 (2011)
    Advances in genotyping and sequencing technologies have revolutionized the genetics of complex disease by locating rare and common variants that influence an individual's risk for diseases, such as diabetes, cancers, and psychiatric disorders. However, to capitalize on these data for prevention and therapies requires the identification of causal alleles and a mechanistic understanding for how these variants contribute to the disease. After discussing the strategies currently used to map variants for complex diseases, this Primer explores how variants may be prioritized for follow-up functional studies and the challenges and approaches for assessing the contributions of rare and common variants to disease phenotypes.
  • Modeling Human Disease in Humans: The Ciliopathies
    - Cell 147(1):70-79 (2011)
    Soon, the genetic basis of most human Mendelian diseases will be solved. The next challenge will be to leverage this information to uncover basic mechanisms of disease and develop new therapies. To understand how this transformation is already beginning to unfold, we focus on the ciliopathies, a class of multi-organ diseases caused by disruption of the primary cilium. Through a convergence of data involving mutant gene discovery, proteomics, and cell biology, more than a dozen phenotypically distinguishable conditions are now united as ciliopathies. Sitting at the interface between simple and complex genetic conditions, these diseases provide clues to the future direction of human genetics.
  • The Lin28/let-7 Axis Regulates Glucose Metabolism
    - Cell 147(1):81-94 (2011)
    The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data! establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.
  • Translocation-Capture Sequencing Reveals the Extent and Nature of Chromosomal Rearrangements in B Lymphocytes
    - Cell 147(1):95-106 (2011)
    Chromosomal rearrangements, including translocations, require formation and joining of DNA double strand breaks (DSBs). These events disrupt the integrity of the genome and are frequently involved in producing leukemias, lymphomas and sarcomas. Despite the importance of these events, current understanding of their genesis is limited. To examine the origins of chromosomal rearrangements we developed Translocation Capture Sequencing (TC-Seq), a method to document chromosomal rearrangements genome-wide, in primary cells. We examined over 180,000 rearrangements obtained from 400 million B lymphocytes, revealing that proximity between DSBs, transcriptional activity and chromosome territories are key determinants of genome rearrangement. Specifically, rearrangements tend to occur in cis and to transcribed genes. Finally, we find that activation-induced cytidine deaminase (AID) induces the rearrangement of many genes found as translocation partners in mature B cell lymphoma.
  • Genome-wide Translocation Sequencing Reveals Mechanisms of Chromosome Breaks and Rearrangements in B Cells
    - Cell 147(1):107-119 (2011)
    Whereas chromosomal translocations are common pathogenetic events in cancer, mechanisms that promote them are poorly understood. To elucidate translocation mechanisms in mammalian cells, we developed high-throughput, genome-wide translocation sequencing (HTGTS). We employed HTGTS to identify tens of thousands of independent translocation junctions involving fixed I-SceI meganuclease-generated DNA double-strand breaks (DSBs) within the c-myc oncogene or IgH locus of B lymphocytes induced for activation-induced cytidine deaminase (AID)-dependent IgH class switching. DSBs translocated widely across the genome but were preferentially targeted to transcribed chromosomal regions. Additionally, numerous AID-dependent and AID-independent hot spots were targeted, with the latter comprising mainly cryptic I-SceI targets. Comparison of translocation junctions with genome-wide nuclear run-ons revealed a marked association between transcription start sites and translocation targeti! ng. The majority of translocation junctions were formed via end-joining with short microhomologies. Our findings have implications for diverse fields, including gene therapy and cancer genomics.
  • A DNA Repair Complex Functions as an Oct4/Sox2 Coactivator in Embryonic Stem Cells
    - Cell 147(1):120-131 (2011)
    The transcriptional activators Oct4, Sox2, and Nanog cooperate with a wide array of cofactors to orchestrate an embryonic stem (ES) cell-specific gene expression program that forms the molecular basis of pluripotency. Here, we report using an unbiased in vitro transcription-biochemical complementation assay to discover a multisubunit stem cell coactivator complex (SCC) that is selectively required for the synergistic activation of the Nanog gene by Oct4 and Sox2. Purification, identification, and reconstitution of SCC revealed this coactivator to be the trimeric XPC-nucleotide excision repair complex. SCC interacts directly with Oct4 and Sox2 and is recruited to the Nanog and Oct4 promoters as well as a majority of genomic regions that are occupied by Oct4 and Sox2. Depletion of SCC/XPC compromised both pluripotency in ES cells and somatic cell reprogramming of fibroblasts to induced pluripotent stem (iPS) cells. This study identifies a transcriptional coactivator with! diversified functions in maintaining ES cell pluripotency and safeguarding genome integrity. PaperClip View Within Article
  • An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming
    - Cell 147(1):132-146 (2011)
    Alternative splicing (AS) is a key process underlying the expansion of proteomic diversity and the regulation of gene expression. Here, we identify an evolutionarily conserved embryonic stem cell (ESC)-specific AS event that changes the DNA-binding preference of the forkhead family transcription factor FOXP1. We show that the ESC-specific isoform of FOXP1 stimulates the expression of transcription factor genes required for pluripotency, including OCT4, NANOG, NR5A2, and GDF3, while concomitantly repressing genes required for ESC differentiation. This isoform also promotes the maintenance of ESC pluripotency and contributes to efficient reprogramming of somatic cells into induced pluripotent stem cells. These results reveal a pivotal role for an AS event in the regulation of pluripotency through the control of critical ESC-specific transcriptional programs.
  • Selective Translation of Leaderless mRNAs by Specialized Ribosomes Generated by MazF in Escherichia coli
    - Cell 147(1):147-157 (2011)
    Escherichia coli (E. coli) mazEF is a stress-induced toxin-antitoxin (TA) module. The toxin MazF is an endoribonuclease that cleaves single-stranded mRNAs at ACA sequences. Here, we show that MazF cleaves at ACA sites at or closely upstream of the AUG start codon of some specific mRNAs and thereby generates leaderless mRNAs. Moreover, we provide evidence that MazF also targets 16S rRNA within 30S ribosomal subunits at the decoding center, thereby removing 43 nucleotides from the 3′ terminus. As this region comprises the anti-Shine-Dalgarno (aSD) sequence that is required for translation initiation on canonical mRNAs, a subpopulation of ribosomes is formed that selectively translates the described leaderless mRNAs both in vivo and in vitro. Thus, we have discovered a modified translation machinery that is generated in response to MazF induction and that probably serves for stress adaptation in Escherichia coli.
  • Regulatory Control of the Resolution of DNA Recombination Intermediates during Meiosis and Mitosis
    - Cell 147(1):158-172 (2011)
    The efficient and timely resolution of DNA recombination intermediates is essential for bipolar chromosome segregation. Here, we show that the specialized chromosome segregation patterns of meiosis and mitosis, which require the coordination of recombination with cell-cycle progression, are achieved by regulating the timing of activation of two crossover-promoting endonucleases. In yeast meiosis, Mus81-Mms4 and Yen1 are controlled by phosphorylation events that lead to their sequential activation. Mus81-Mms4 is hyperactivated by Cdc5-mediated phosphorylation in meiosis I, generating the crossovers necessary for chromosome segregation. Yen1 is also tightly regulated and is activated in meiosis II to resolve persistent Holliday junctions. In yeast and human mitotic cells, a similar regulatory network restrains these nuclease activities until mitosis, biasing the outcome of recombination toward noncrossover products while also ensuring the elimination of any persistent jo! int molecules. Mitotic regulation thereby facilitates chromosome segregation while limiting the potential for loss of heterozygosity and sister-chromatid exchanges.
  • Saturated Fatty Acids Induce c-Src Clustering within Membrane Subdomains, Leading to JNK Activation
    - Cell 147(1):173-184 (2011)
    Saturated fatty acids (FA) exert adverse health effects and are more likely to cause insulin resistance and type 2 diabetes than unsaturated FA, some of which exert protective and beneficial effects. Saturated FA, but not unsaturated FA, activate Jun N-terminal kinase (JNK), which has been linked to obesity and insulin resistance in mice and humans. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and inhibit insulin signaling through c-Src activation. FA alter the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains, where it likely becomes activated. Conversely, unsaturated FA with known beneficial effects on glucose metabolism prevent c-Src membrane partitioning and activation, which are dependent on its myristoylation, and block JNK activation. Consumption of a diabetogenic high-fat diet causes the partitioning and activation of c-Src within deterge! nt insoluble membrane subdomains of murine adipocytes.
  • Conformation-Sensing Antibodies Stabilize the Oxidized Form of PTP1B and Inhibit Its Phosphatase Activity
    - Cell 147(1):185-198 (2011)
    Protein tyrosine phosphatase 1B (PTP1B) plays important roles in downregulation of insulin and leptin signaling and is an established therapeutic target for diabetes and obesity. PTP1B is regulated by reactive oxygen species (ROS) produced in response to various stimuli, including insulin. The reversibly oxidized form of the enzyme (PTP1B-OX) is inactive and undergoes profound conformational changes at the active site. We generated conformation-sensor antibodies, in the form of single-chain variable fragments (scFvs), that stabilize PTP1B-OX and thereby inhibit its phosphatase function. Expression of conformation-sensor scFvs as intracellular antibodies (intrabodies) enhanced insulin-induced tyrosyl phosphorylation of the β subunit of the insulin receptor and its substrate IRS-1 and increased insulin-induced phosphorylation of PKB/AKT. Our data suggest that stabilization of the oxidized, inactive form of PTP1B with appropriate therapeutic molecules may offer a paradig! m for phosphatase drug development.
  • Crystal Structure of the Mammalian GIRK2 K+ Channel and Gating Regulation by G Proteins, PIP2, and Sodium
    - Cell 147(1):199-208 (2011)
    G protein-gated K+ channels (Kir3.1–Kir3.4) control electrical excitability in many different cells. Among their functions relevant to human physiology and disease, they regulate the heart rate and govern a wide range of neuronal activities. Here, we present the first crystal structures of a G protein-gated K+ channel. By comparing the wild-type structure to that of a constitutively active mutant, we identify a global conformational change through which G proteins could open a G loop gate in the cytoplasmic domain. The structures of both channels in the absence and presence of PIP2 suggest that G proteins open only the G loop gate in the absence of PIP2, but in the presence of PIP2 the G loop gate and a second inner helix gate become coupled, so that both gates open. We also identify a strategically located Na+ ion-binding site, which would allow intracellular Na+ to modulate GIRK channel activity. These data provide a structural basis for understanding multiligand r! egulation of GIRK channel gating.
  • A Pseudoatomic Model of the Dynamin Polymer Identifies a Hydrolysis-Dependent Powerstroke
    - Cell 147(1):209-222 (2011)
    The GTPase dynamin catalyzes membrane fission by forming a collar around the necks of clathrin-coated pits, but the specific structural interactions and conformational changes that drive this process remain a mystery. We present the GMPPCP-bound structures of the truncated human dynamin 1 helical polymer at 12.2 Å and a fusion protein, GG, linking human dynamin 1's catalytic G domain to its GTPase effector domain (GED) at 2.2 Å. The structures reveal the position and connectivity of dynamin fragments in the assembled structure, showing that G domain dimers only form between tetramers in sequential rungs of the dynamin helix. Using chemical crosslinking, we demonstrate that dynamin tetramers are made of two dimers, in which the G domain of one molecule interacts in trans with the GED of another. Structural comparison of GGGMPPCP to the GG transition-state complex identifies a hydrolysis-dependent powerstroke that may play a role in membrane-remodeling events necessary! for fission.
  • Beclin1 Controls the Levels of p53 by Regulating the Deubiquitination Activity of USP10 and USP13
    - Cell 147(1):223-234 (2011)
    Autophagy is an important intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles. We report a potent small molecule inhibitor of autophagy named "spautin-1" for specific and potent autophagy inhibitor-1. Spautin-1 promotes the degradation of Vps34 PI3 kinase complexes by inhibiting two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes. Beclin1 is a tumor suppressor and frequently monoallelically lost in human cancers. Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. Since USP10 mediates the deubiquitination of p53, regulating deubiquitination activity of USP10 and USP13 by Beclin1 provides a mechanism for Beclin1 to control the levels of p53. Our study provides a molecular mechanism involving protein deubiquitination that connects two important tumor suppressors, p53 and Beclin1, and a poten! t small molecule inhibitor of autophagy as a possible lead compound for developing anticancer drugs.
  • Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits
    - Cell 147(1):235-246 (2011)
    Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2−/− mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in bra! in development and provide a new tool for mechanistic and therapeutic research in ASD. PaperFlick View Within Article
  • AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias
    - Cell 147(1):247 (2011)
  • SnapShot: Human Biomedical Genomics
    - Cell 147(1):248-248.e1 (2011)

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