TRIM24 links a non-canonical histone signature to breast cancer

Recognition of modified histone species by distinct structural domains within 'reader' proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis.     

An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division

RNA interference (RNAi) is an evolutionarily conserved defence mechanism whereby genes are specifically silenced through degradation of messenger RNAs; this process is mediated by homologous double-stranded (ds)RNA molecules. In invertebrates, long dsRNAs have been used for genome-wide screens and have provided insights into gene functions. Because long dsRNA triggers a nonspecific interferon response in many vertebrates, short interfering (si)RNA or short hairpin (sh)RNAs must be used for these organisms to ensure specific gene silencing. Here we report the generation of a genome-scale library of endoribonuclease-prepared short interfering (esi)RNAs from a sequence-verified complementary DNA collection representing 15,497 human genes. We used 5,305 esiRNAs from this library to screen for genes required for cell division in HeLa cells. Using a primary high-throughput cell viability screen followed by a secondary high content videomicroscopy assay, we identified 37 genes required for cell division. These include several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. Thus, our study uncovers new aspects of cell division and establishes esiRNA as a versatile approach for genomic RNAi screens in mammalian cells.     

Thermal ecology,activity pattern,habitat, and microhabitats used by the skink Mabuya arajara (Squamata: Scincidae) in the Araripe Plateau,northeastern Brazil

ABSTRACT

We evaluated the activity period, thermal ecology, habitats, and preference for microhabitats of the skink Mabuya arajara in a humid forest environment on the slope of the Araripe Plateau, Brazil. A total of 283 lizards were observed. The lizards were found to be diurnally active (unimodal type pattern), with peak activity during the hottest hours of the day (1100 to 1200). About habitat use, the majority of individuals (73.8% N = 209) were recorded in the narrow transitional area, in the edges of the forest; while 26.4% of individuals were observed in open areas and no observations were made in dense forest. Seven different types of microhabitats were used, with fallen palm leaves (Arecaceae) being the preferred (47.7% N = 135). Considering all lizards, microhabitat niche breadth was 3.27. Males and females presented a high overlap (0.95) in microhabitat use. The average T_c recorded for M. arajara was 32.06 ± 2.72°C. Body size (SVL) did not influence body temperature (F = 0.51, P = > 0.05). Most of the animals were observed with their bodies completely exposed (67.84%, N = 192), 18.37% (N = 52) were semi-exposed and 13.79% (N = 39) were in shelters. Among animals with some degree of sunlight exposure, 57.59% (N = 163) were in shadows, 25.10% (N = 71) were under sunlight filtered by vegetation, and 17.31% (N = 49) were under direct sunlight.A review of the ecology of Mabuya spp. shows that several features appear to be conserved among members of the genus.     

The hyh mutation uncovers roles for alpha Snap in apical protein localization and control of neural cell fate

The hyh (hydrocephalus with hop gait) mouse shows a markedly small cerebral cortex at birth and dies postnatally from progressive enlargement of the ventricular system. Here we show that the small hyh cortex reflects altered cell fate. Neural progenitor cells withdraw prematurely from the cell cycle, producing more early-born, deep-layer cerebral cortical neurons but depleting the cortical progenitor pool, such that late-born, upper-layer cortical neurons are underproduced, creating a small cortex. hyh mice carry a hypomorphic missense mutation in the gene Napa encoding soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein alpha (alpha Snap), involved in SNAP receptor (SNARE)-mediated vesicle fusion in many cellular contexts. A targeted null Napa mutation is embryonically lethal. Altered neural cell fate is accompanied by abnormal localization of many apical proteins implicated in regulation of neural cell fate, including E-cadherin, beta-catenin, atypical protein kinase C (aPKC) and INADL (inactivation-no-afterpotential D-like, also known as protein associated with Lin7, or Pals1). Apical localization of the SNARE Vamp7 is also disrupted. Thus, alpha Snap is essential for apical protein localization and cell fate determination in neuroepithelial cells.     

Pervasive alteration of tree communities in undisturbed Amazonian forests

Amazonian rainforests are some of the most species-rich tree communities on earth. Here we show that, over the past two decades, forests in a central Amazonian landscape have experienced highly nonrandom changes in dynamics and composition. Our analyses are based on a network of 18 permanent plots unaffected by any detectable disturbance. Within these plots, rates of tree mortality, recruitment and growth have increased over time. Of 115 relatively abundant tree genera, 27 changed significantly in population density or basal area--a value nearly 14 times greater than that expected by chance. An independent, eight-year study in nearby forests corroborates these shifts in composition. Contrary to recent predictions, we observed no increase in pioneer trees. However, genera of faster-growing trees, including many canopy and emergent species, are increasing in dominance or density, whereas genera of slower-growing trees, including many subcanopy species, are declining. Rising atmospheric CO2 concentrations may explain these changes, although the effects of this and other large-scale environmental alterations remain uncertain. These compositional changes could have important impacts on the carbon storage, dynamics and biota of Amazonian forests.     

Integrated detection and population-genetic analysis of SNPs and copy number variation

Dissecting the genetic basis of disease risk requires measuring all forms of genetic variation, including SNPs and copy number variants (CNVs), and is enabled by accurate maps of their locations, frequencies and population-genetic properties. We designed a hybrid genotyping array (Affymetrix SNP 6.0) to simultaneously measure 906,600 SNPs and copy number at 1.8 million genomic locations. By characterizing 270 HapMap samples, we developed a map of human CNV (at 2-kb breakpoint resolution) informed by integer genotypes for 1,320 copy number polymorphisms (CNPs) that segregate at an allele frequency >1%. More than 80% of the sequence in previously reported CNV regions fell outside our estimated CNV boundaries, indicating that large (>100 kb) CNVs affect much less of the genome than initially reported. Approximately 80% of observed copy number differences between pairs of individuals were due to common CNPs with an allele frequency >5%, and more than 99% derived from inheritance rather than new mutation. Most common, diallelic CNPs were in strong linkage disequilibrium with SNPs, and most low-frequency CNVs segregated on specific SNP haplotypes.     

Clustering and clique partitioning: Simulated annealing and tabu search approaches

We study the application of simulated annealing and tabu search to the solution of the clique partitioning problem. We illustrate the effecveness of these techniques by computational results associated not only with randomly generated problems, but also with real-life problems arising from applications concerning the optimal aggregation of binary relations into an equivalence relation. The need for these approaches is emphasized by the example of a special class of instances of the clique partitioning problem for which the most commonly used heuristics perform arbitrarily badly, while tabu search systematically obtains the optimal solution.

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Résumé Nous étudions dans cet article l'application du recuit simulé et de la méthode de recherche tabou dans la résolution du problème de partitionnement de graphes en cliques. Nous illustrons l'efficacité de ces techniques par des résultats numériques associés soit à des problèmes génerés au hasard, soit à des problèmes réels concernant l'agrégation de relations binaires dans une relation d'équivalence. L'intérêt de ces approches est mis en évidence à travers une classe de problèmes pour lesquels les heuristiques les plus connues ont une performance arbitrairement mauvaise, tandis que la méthode de recherche tabou obtient systématiquement des solutions optimales.

     

Mapping determinants of human gene expression by regional and genome-wide association

To study the genetic basis of natural variation in gene expression, we previously carried out genome-wide linkage analysis and mapped the determinants of approximately 1,000 expression phenotypes. In the present study, we carried out association analysis with dense sets of single-nucleotide polymorphism (SNP) markers from the International HapMap Project. For 374 phenotypes, the association study was performed with markers only from regions with strong linkage evidence; these regions all mapped close to the expressed gene. For a subset of 27 phenotypes, analysis of genome-wide association was performed with >770,000 markers. The association analysis with markers under the linkage peaks confirmed the linkage results and narrowed the candidate regulatory regions for many phenotypes with strong linkage evidence. The genome-wide association analysis yielded highly significant results that point to the same locations as the genome scans for about 50% of the phenotypes. For one candidate determinant, we carried out functional analyses and confirmed the variation in cis-acting regulatory activity. Our findings suggest that association studies with dense SNP maps will identify susceptibility loci or other determinants for some complex traits or diseases.