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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.06.040 Byline: Maite Huarte (1)(2), Mitchell Guttman (1)(3), David Feldser (3)(4), Manuel Garber (1), Magdalena J. Koziol (1)(2), Daniela Kenzelmann-Broz (5)(6), Ahmad M. Khalil (1)(2), Or Zuk (1), Ido Amit (1), Michal Rabani (1), Laura D. Attardi (5)(6), Aviv Regev (1)(3), Eric S. Lander (1)(3)(7), Tyler Jacks (3)(4), John L. Rinn (1)(2) Keywords: RNA; CELLCYCLE Abstract: Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes. Author Affiliation: (1) The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA (2) Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA (3) Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA (4) The Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA (5) Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA (6) Department of and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA (7) Department of Systems Biology, Harvard Medical School, Boston, MA 02114, USA Article History: Received 6 October 2009; Revised 6 April 2010; Accepted 3 June 2010 Article Note: (miscellaneous) Published online: July 29, 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.05.028 Byline: Xiaoying Bai (1)(2)(3), Jonghwan Kim (1)(3)(4), Zhongan Yang (5), Michael J. Jurynec (6), Thomas E. Akie (3), Joseph Lee (1)(2)(3), Jocelyn LeBlanc (1)(2)(3), Anna Sessa (1)(2)(3), Hong Jiang (5), Anthony DiBiase (1)(2)(3), Yi Zhou (1)(2)(3), David J. Grunwald (6), Shuo Lin (5), Alan B. Cantor (3), Stuart H. Orkin (1)(3)(4), Leonard I. Zon (1)(2)(3) Keywords: DEV BIO; RNA Abstract: Recent genome-wide studies have demonstrated that pausing of RNA polymerase II (Pol II) occurred on many vertebrate genes. By genetic studies in the zebrafish tif1[gamma] mutant moonshine we found that loss of function of Pol II-associated factors PAF or DSIF rescued erythroid gene transcription in tif1[gamma]-deficient animals. Biochemical analysis established physical interactions among TIF1[gamma], the blood-specific SCL transcription complex, and the positive elongation factors p-TEFb and FACT. Chromatin immunoprecipitation assays in human CD34.sup.+ cells supported a TIF1[gamma]-dependent recruitment of positive elongation factors to erythroid genes to promote transcription elongation by counteracting Pol II pausing. Our study establishes a mechanism for regulating tissue cell fate and differentiation through transcription elongation. Author Affiliation: (1) Howard Hughes Medical Institute, Boston, MA 02115, USA (2) Stem Cell Program, Children's Hospital Boston, Boston, MA 02115, USA (3) Division of Hematology/Oncology, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA (4) Department of Pediatric Oncology, The Dana Farber Cancer Institute, Boston, MA 02115, USA (5) Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA (6) Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA Article History: Received 13 November 2009; Revised 23 February 2010; Accepted 14 April 2010 Article Note: (miscellaneous) Published: July 8, 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.05.020 Byline: Rebecca C. Iskow (1)(2), Michael T. McCabe (3)(6), Ryan E. Mills (2), Spencer Torene (2), W. Stephen Pittard (7), Andrew F. Neuwald (8)(9), Erwin G. Van Meir (4)(5)(6), Paula M. Vertino (1)(3)(6), Scott E. Devine (1)(2)(6)(8)(10)(11) Keywords: DNA; EVO_ECOL; HUMDISEASE Abstract: Two abundant classes of mobile elements, namely Alu and L1 elements, continue to generate new retrotransposon insertions in human genomes. Estimates suggest that these elements have generated millions of new germline insertions in individual human genomes worldwide. Unfortunately, current technologies are not capable of detecting most of these young insertions, and the true extent of germline mutagenesis by endogenous human retrotransposons has been difficult to examine. Here, we describe technologies for detecting these young retrotransposon insertions and demonstrate that such insertions indeed are abundant in human populations. We also found that new somatic L1 insertions occur at high frequencies in human lung cancer genomes. Genome-wide analysis suggests that altered DNA methylation may be responsible for the high levels of L1 mobilization observed in these tumors. Our data indicate that transposon-mediated mutagenesis is extensive in human genomes and is likely to have a major impact on human biology and diseases. Author Affiliation: (1) Genetics and Molecular Biology Graduate Program, Emory University, Atlanta, GA 30322, USA (2) Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA (3) Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA (4) Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA (5) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA (6) Winship Cancer Institute, University of Maryland School of Medicine, Baltimore, MD 20201, USA (7) Bimcore, Emory University, Atlanta, GA 30322, USA (8) Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 20201, USA (9) Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 20201, USA (10) Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 20201, USA (11) Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 20201, USA Article History: Received 15 January 2010; Revised 1 April 2010; Accepted 12 May 2010 Article Note: (miscellaneous) Published: June 24, 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.01.011 Byline: Bernike Kalverda (1), Helen Pickersgill (1), Victor V. Shloma (2), Maarten Fornerod (1) Keywords: CELLBIO; RNA; DNA Abstract: Nuclear pore complexes (NPCs) mediate transport across the nuclear envelope. In yeast, they also interact with active genes, attracting or retaining them at the nuclear periphery. In higher eukaryotes, some NPC components (nucleoporins) are also found in the nucleoplasm, with a so far unknown function. We have functionally characterized nucleoporin-chromatin interactions specifically at the NPC or within the nucleoplasm in Drosophila. We analyzed genomic interactions of full-length nucleoporins Nup98, Nup50, and Nup62 and nucleoplasmic and NPC-tethered forms of Nup98. We found that nucleoporins predominantly interacted with transcriptionally active genes inside the nucleoplasm, in particular those involved in developmental regulation and the cell cycle. A smaller set of nonactive genes interacted with the NPC. Genes strongly interacting with nucleoplasmic Nup98 were downregulated upon Nup98 depletion and activated on nucleoplasmic Nup98 overexpression. Thus, nucleoporins stimulate developmental and cell-cycle gene expression away from the NPC by interacting with these genes inside the nucleoplasm. Author Affiliation: (1) Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (2) Department of Molecular and Cellular Biology, Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences, Novosibirsk 630090, Russia Article History: Received 18 May 2009; Revised 18 May 2009; Accepted 31 December 2009 Article Note: (miscellaneous) Published: February 4, 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.12.001 Byline: Stefan Klumpp (1)(2)(4), Zhongge Zhang (3), Terence Hwa (1)(2)(3) Keywords: CELLBIO Abstract: Bacterial gene expression depends not only on specific regulatory mechanisms, but also on bacterial growth, because important global parameters such as the abundance of RNA polymerases and ribosomes are all growth-rate dependent. Understanding of these global effects is necessary for a quantitative understanding of gene regulation and for the design of synthetic genetic circuits. We find that the observed growth-rate dependence of constitutive gene expression can be explained by a simple model using the measured growth-rate dependence of the relevant cellular parameters. More complex growth dependencies for genetic circuits involving activators, repressors, and feedback control were analyzed and verified experimentally with synthetic circuits. Additional results suggest a feedback mechanism mediated by general growth-dependent effects that does not require explicit gene regulation if the expressed protein affects cell growth. This mechanism can lead to growth bistability and promote the acquisition of important physiological functions such as antibiotic resistance and tolerance (persistence). Author Affiliation: (1) Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA 92093-0374, USA (2) Department of Physics, University of California, San Diego, La Jolla, CA 92093-0374, USA (3) Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0374, USA (4) Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany Article History: Received 7 April 2009; Revised 1 September 2009; Accepted 1 December 2009 Article Note: (miscellaneous) Published: December 24, 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.12.002 Byline: Jamy C. Peng (1), Anton Valouev (2), Tomek Swigut (1), Junmei Zhang (5), Yingming Zhao (6), Arend Sidow (2)(3), Joanna Wysocka (1)(4) Keywords: STEMCELL; DEVBIO; PROTEINS Abstract: Polycomb Repressive Complex 2 (PRC2) regulates key developmental genes in embryonic stem (ES) cells and during development. Here we show that Jarid2/Jumonji, a protein enriched in pluripotent cells and a founding member of the Jumonji C (JmjC) domain protein family, is a PRC2 subunit in ES cells. Genome-wide ChIP-seq analyses of Jarid2, Ezh2, and Suz12 binding reveal that Jarid2 and PRC2 occupy the same genomic regions. We further show that Jarid2 promotes PRC2 recruitment to the target genes while inhibiting PRC2 histone methyltransferase activity, suggesting that it acts as a 'molecular rheostat' that finely calibrates PRC2 functions at developmental genes. Using Xenopus laevis as a model we demonstrate that Jarid2 knockdown impairs the induction of gastrulation genes in blastula embryos and results in failure of differentiation. Our findings illuminate a mechanism of histone methylation regulation in pluripotent cells and during early cell-fate transitions. Author Affiliation: (1) Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA (2) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA (3) Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA (4) Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA (5) Protein Chemistry Technology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA (6) Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA Article History: Received 3 June 2009; Revised 17 August 2009; Accepted 1 December 2009 Article Note: (miscellaneous) Published: December 24, 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.10.025 Byline: Tobias Bollenbach (1), Selwyn Quan (3), Remy Chait (1), Roy Kishony (1)(2) Keywords: MICROBIO; SYSBIO Abstract: Suppressive drug interactions, in which one antibiotic can actually help bacterial cells to grow faster in the presence of another, occur between protein and DNA synthesis inhibitors. Here, we show that this suppression results from nonoptimal regulation of ribosomal genes in the presence of DNA stress. Using GFP-tagged transcription reporters in Escherichia coli, we find that ribosomal genes are not directly regulated by DNA stress, leading to an imbalance between cellular DNA and protein content. To test whether ribosomal gene expression under DNA stress is nonoptimal for growth rate, we sequentially deleted up to six of the seven ribosomal RNA operons. These synthetic manipulations of ribosomal gene expression correct the protein-DNA imbalance, lead to improved survival and growth, and completely remove the suppressive drug interaction. A simple mathematical model explains the nonoptimal regulation of ribosomal genes under DNA stress as a side effect of their optimal regulation in different nutrient environments. These results reveal the genetic mechanism underlying an important class of suppressive drug interactions. Author Affiliation: (1) Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA (2) School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA (3) Department of Chemical and Systems Biology, Stanford University, 318 Campus Drive, Stanford, CA 94305, USA Article History: Received 23 March 2009; Revised 15 June 2009; Accepted 14 October 2009 Article Note: (miscellaneous) Published: November 12, 2009

Anopheles mosquitoes are major vectors of human malaria in Africa that transmits malaria parasites. The hemocyte-specific complement-like protein TEP1 from mosquito Anopheles gambiae that binds to and mediates killing of midgut stages of the rodent malaria parasite Plasmodium berghei is reported.