Single nucleotide variants in transcription factors associate more tightly with phenotype than with gene expression

Mapping the polymorphisms responsible for variation in gene expression, known as Expression Quantitative Trait Loci (eQTL), is a common strategy for investigating the molecular basis of disease. Despite numerous eQTL studies, the relationship between the explanatory power of variants on gene expression versus their power to explain ultimate phenotypes remains to be clarified. We addressed this question using four naturally occurring Quantitative Trait Nucleotides (QTN) in three transcription factors that affect sporulation efficiency in wild strains of the yeast, Saccharomyces cerevisiae. We compared the ability of these QTN to explain the variation in both gene expression and sporulation efficiency. We find that the amount of gene expression variation explained by the sporulation QTN is not predictive of the amount of phenotypic variation explained. The QTN are responsible for 98% of the phenotypic variation in our strains but the median gene expression variation explained is only 49%. The alleles that are responsible for most of the variation in sporulation efficiency do not explain most of the variation in gene expression. The balance between the main effects and gene-gene interactions on gene expression variation is not the same as on sporulation efficiency. Finally, we show that nucleotide variants in the same transcription factor explain the expression variation of different sets of target genes depending on whether the variant alters the level or activity of the transcription factor. Our results suggest that a subset of gene expression changes may be more predictive of ultimate phenotypes than the number of genes affected or the total fraction of variation in gene expression variation explained by causative variants, and that the downstream phenotype is buffered against variation in the gene expression network

Helix vs. Sheet Formation in a Small Peptide

Segments with the amino acid sequence EKAYLRT appear in natural occurring proteins both in $\alpha$-helices and $\beta$-sheets. For this reason, we have use this peptide to study how secondary structure formation in proteins depends on the local environment. Our data rely on multicanonical Monte Carlo simulations where the interactions among all atoms are taken into account. Results in gas phase are compared with that in an implicit solvent. We find that both in gas phase and solvated EKAYLRT forms an $\alpha$-helix when not interacting with other molecules. However, in the vicinity of a $\beta$-strand, the peptide forms a $\beta$-strand. Because of this change in secondary structure our peptide may provide a simple model for the $\alpha \to \beta$ transition that is supposedly related to the outbreak of Prion diseases and similar illnesses.Comment: to appear in Physical Review

Target company cross-border effects in acquisitions into the UK

We analyse the abnormal returns to target shareholders in crossborder and domestic acquisitions of UK companies. The crossborder effect during the bid month is small (0.84%), although crossborder targets gain significantly more than domestic targets during the months surrounding the bid. We find no evidence for the level of abnormal returns in crossborder acquisitions to be associated with market access or exchange rate effects, and only limited support for an international diversification effect. However, the crossborder effect appears to be associated with significant payment effects, and there is no significant residual crossborder effect once various bid characteristics are controlled for

Nitroimidazoles: Part XI. Some Halonitro- & dinitroimidazoles

Methylation of 2-chloro-4-nitroimidazole (6), obtained from imidazole in four steps, either with dimethyl sulphate or with diazomethane affords a mixture of 2-chloro-l-methyl-5-nitroimidazole (10) and the 4-nitro-isomer (7). The corresponding dinitro compounds 11 and 8 are formed in the methylation of 2,4-dinitroimidazole (5), 8 being converted to 7 by the action of POCl3. Reaction of 10 with the sodium salt of N-methanesulphonyl-2-imidazolidinone provides the potent amoebicide, 1-methylsulphonyl-3-(1-methyl-5-nitroimidazol-2-yl)-2-imidazolidinone (2). The isomer 14 is synthesised from 7 in low yield. Ethylation of 5 leads to preponderant N-alkylation, providing a mixture of l-ethyldinitroimidazoles (9) and (12), but a small amount of N,C-diethyl derivative 15 is also obtained. The formation of 15 from 5 is rationalised. The diiodination product of imidazole is shown to be 4,5-diiodoimidazole (19), nitric acid transforming it to 4-iodo-5-nitroimidazole (20). Methylation of 20 affords a mixture of isomeric 1 -methyliodonitro derivatives (21) and (22). The structures of 21 and 22 are established by 13C NMR data as well as by conversion into morpholine derivatives 26 and 24 respectively which also arise from 1-methylchloronitroimidazoles (25) and (23). A mechanism is proposed for the reported conversion of 5 into 4-chloro-5-nitroimidazole (32) in boiling 2-chloroethanol

Nitroimidazoles: Part VIII. 2-Amino-1-methyl-5-nitroimidazoles & derivatives

Treatment of 1-methyl-2-methylsulphonyl-5-nitroimidazole (3) with liquid ammonia gives 2-amino-l-methyl-5-nitroimidazole(2). With sodamide and 3, the major product is the sulphone(4). 2 is transformed by isocyanates into ureas(5a-c), while with 2-chloroethyl isocyanate, imidazolidinone (6) and aminooxazolinone (7) are obtained. 2 is less reactive towards isothiocyanates and gives under forcing conditions, thioureas (8a, b) and guanidines (9a, b). Amides (lOa-c) are obtained from 2 by acylation and lOd-g from sulphone(3) by displacement reactions as also sulphamides(lla-c). Cyclic anhydrides and 2 lead to imides (13-15). 2 is transformed into schiff bases (16a-k), some of them being reduced by sodium borohydride to aralkyl amines (17a-c). The ethoxymethylene derivative (18) of 2 is transformed into a large number of formamidines (19a-r), (20a-c) and 21, some of them being further converted into the dichloroacetyl derivatives (22a-c). Reaction of 18 with sodium borohydride affords the ethoxymethylamine (23b) and methylamine derivative (23a). The latter is available from 2 along with dimethylamine (23c) by alkylation with methyl iodide. A less satisfactory route for 23a and 23c is displacement of sulphone group from 3 by appropriate amine. Analogous displacements on 3 provide the derivatives 23d, e and 24. The product from the reaction of 3 with sodium azide is the azido derivative (25). The aziridine (27) undergoes iodide-catalysed ring opening to form 29a and does not rearrange to the imidazoline (28). The amirioethanol derivative (29b) results from 27 by an acid-catalysed reaction

A novel mechanism for target gene-specific SWI/SNF recruitment via the Snf2p N-terminus

Chromatin-remodeling complexes regulate the expression of genes in all eukaryotic genomes. The SWI/SNF complex of Saccharomyces cerevisiae is recruited to its target promoters via interactions with selected transcription factors. Here, we show that the N-terminus of Snf2p, the chromatin remodeling core unit of the SWI/SNF complex, is essential for the expression of VHT1, the gene of the plasma membrane H+/biotin symporter, and of BIO5, the gene of a 7-keto-8-aminopelargonic acid transporter, biotin biosynthetic precursor. chromatin immunoprecipitation (ChIP) analyses demonstrate that Vhr1p, the transcriptional regulator of VHT1 and BIO5 expression, is responsible for the targeting of Snf2p to the VHT1 promoter at low biotin. We identified an Snf2p mutant, Snf2p-R15C, that specifically abolishes the induction of VHT1 and BIO5 but not of other Snf2p-regulated genes, such as GAL1, SUC2 or INO1. We present a novel mechanism of target gene-specific SWI/SNF recruitment via Vhr1p and a conserved N-terminal Snf2p domain

Hansenula polymorpha Swi1p and Snf2p are essential for methanol utilisation

We have cloned the Hansenula polymorpha SWI1 and SNF2 genes by functional complementation of mutants that are defective in methanol utilisation. These genes encode proteins similar to Saccharomyces cerevisiae Swi1p and Snf2p, which are subunits of the SWI/SNF complex. This complex belongs to the family of nucleosome-remodeling complexes that play a role in transcriptional control of gene expression. Analysis of the phenotypes of constructed H. polymorpha SWI1 and SNF2 disruption strains indicated that these genes are not necessary for growth of cells on glucose, sucrose, or various organic nitrogen sources which involve the activity of peroxisomal oxidases. Both disruption strains showed a moderate growth defect on glycerol and ethanol, but were fully blocked in methanol utilisation. In methanol-induced cells of both disruption strains, two peroxisomal enzymes involved in methanol metabolism, alcohol oxidase and dihydroxyacetone synthase, were hardly detectable, whereas in wild-type cells these proteins were present at very high levels. We show that the reduction in alcohol oxidase protein levels in H. polymorpha SWI1 and SNF2 disruption strains is due to strongly reduced expression of the alcohol oxidase gene. The level of Pex5p, the receptor involved in import of alcohol oxidase and dihydroxyacetone synthase into peroxisomes, was also reduced in both disruption strains compared to that in wild-type cells.

MicroRNA-211 Expression Promotes Colorectal Cancer Cell Growth In Vitro and In Vivo by Targeting Tumor Suppressor CHD5

Background: Chromodomain-helicase-DNA-binding protein 5 (CHD5) is a newly identified tumor suppressor that is frequently downregulated in a variety of human cancers. Our previous work revealed that the low expression of CHD5 in colorectal cancer is correlated with CHD5 promoter CpG island hypermethylation. In this study, we investigated the effect of microRNA-211 (miR-211)-regulated CHD5 expression on colorectal tumorigenesis. Methodology/Principal Findings: miR-211 was predicted to target CHD5 by TargetScan software analysis. A stably expressing exogenous miR-211 colorectal cancer cell line (HCT-116 miR-211) was generated using lentiviral transduction and used as a model for in vitro and in vivo studies. The expression level of miR-211 in HCT-116 miR-211 cells was upregulated by 16-fold compared to vector control cells (HCT-116 vector). Exogenous miR-211 directly binds to the 39-untranslated region (39-UTR) of CHD5 mRNA, resulting in a 50 % decrease in CHD5 protein level in HCT-116 miR-211 cells. The levels of cell proliferation, tumor growth, and cell migration of HCT-116 miR-211 cells were significantly higher than HCT-116 vector cells under both in vitro and in vivo conditions, as determined using the methods of MTT, colony formation, flow cytometry, scratch assay, and tumor xenografts, respectively. In addition, we found that enforced expression of miR-211 in HCT-116 cells was able to alter p53 pathway-associated regulatory proteins, such as MDM2, Bcl-2, Bcl-xL, and Bax. Conclusion/Significance: Our results demonstrate that CHD5 is a direct target of miR-211 regulation. Enforced expression o