David Martin

GOToolBox: functional analysis of gene datasets based on Gene Ontology

We have developed methods and tools based on the Gene Ontology (GO) resource allowing the identification of statistically over- or under-represented terms in a gene dataset; the clustering of functionally related genes within a set; and the retrieval of genes sharing annotations with a query gene. GO annotations can also be constrained to a slim hierarchy or a given level of the ontology. The source codes are available upon request, and distributed under the GPL license.

Functional classification of proteins for the prediction of cellular function from a protein-protein interaction network

We here describe PRODISTIN, a new computational method allowing the functional clustering of proteins on the basis of protein-protein interaction data. This method, assessed biologically and statistically, enabled us to classify 11% of the Saccharomyces cerevisiae proteome into several groups, the majority of which contained proteins involved in the same biological process(es), and to predict a cellular function for many otherwise uncharacterized proteins.

Genome-wide identification of in vivo Drosophila Engrailed-binding DNA fragments and related target genes.

Chromatin immunoprecipitation after UV crosslinking of DNA/protein interactions was used to construct a library enriched in genomic sequences that bind to the Engrailed transcription factor in Drosophila embryos. Sequencing of the clones led to the identification of 203 Engrailed-binding fragments localized in intergenic or intronic regions. Genes lying near these fragments, which are considered as potential Engrailed target genes, are involved in different developmental pathways, such as anteroposterior patterning, muscle development, tracheal pathfinding or axon guidance. We validated this approach by in vitro and in vivo tests performed on a subset of Engrailed potential targets involved in these various pathways. Finally, we present strong evidence showing that an immunoprecipitated genomic DNA fragment corresponds to a promoter region involved in the direct regulation of frizzled2 expression by engrailed in vivo.

Structural and electrochemical study of metal carbonyl complexes with chelating bis- and tetrakis(diphenylphosphino)tetrathiafulvalenes

Abstract Several mono- and bimetallic complexes involving organometallic fragments such as M(CO)4 (M=Mo, W), Re(CO)3Cl and Fe(CO)3 coordinated to the chelating diphosphine 3,4-dimethyl-3′,4′-bis(diphenylphosphino)tetrathiafulvalene (P2) or tetraphosphine tetrakis(diphenylphosphino)tetrathiafulvalene (P4) have been synthesized and characterized. X-ray diffraction structures have been determined for P4[W(CO)4]2, P2Re(CO)3Cl, P2Fe(CO)3 and P4[Fe(CO)3]2. Octahedral geometries around the metallic center are observed for the tungsten and rhenium complexes, with a fac arrangement of the ligands for the latter, whereas slightly distorted trigonal bipyramid are found for both iron counter parts. Although the complexes are more difficult to oxidize than the corresponding free phosphines, as evidenced by cyclic voltammetry measurements, the first oxidation potentials remain in the usual range, thus offering the opportunity to generate stable radical cation salts. In the case of Fe complexes, the first oxidation wave corresponds to the formation of paramagnetic d7 Fe(I) species, whereas in the Mo, W and Re complexes the metallic center is much more difficult to oxidize than the TTF core.

PRODISTIN Web Site: a tool for the functional classification of proteins from interaction networks

UNLABELLEDnThe PRODISTIN Web Site is a web service allowing users to functionally classify genes/proteins from any type of interaction network. The resulting computation provides a classification tree in which (1) genes/proteins are clustered according to the identity of their interaction partners and (2) functional classes are delineated in the tree using the Biological Process Gene Ontology annotations.nnnAVAILABILITYnThe PRODISTIN Web Site is freely accessible at http://gin.univ-mrs.fr/webdistin

The Advantages of Cyclic Over Acyclic Carbenes To Access Isolable Capto-Dative C-Centered Radicals

A cyclic and an acyclic di(amino)carbene as well as a cyclic and an acyclic (alkyl)(amino)carbene cleanly react with benzoyl chloride to give the corresponding adducts 1+cyc , 1+acy , 2+cyc , and 2+acy , respectively. The reduction of 1+cyc and 2+cyc derived from cyclic carbenes affords the corresponding radicals 1cyc and 2cyc that are stable at room temperature. In contrast, radicals 1acy and 2acy , derived from acyclic carbenes, cannot be isolated. It is shown that 1acy is as thermodynamically stabilized as its cyclic counterpart 1cyc , but its instability is the result of β-hydrogens of the nitrogen substituent, along with the enhanced flexibility around C-N bonds, which allow for a H. -migration-elimination process. Radical 2acy is thermodynamically unstable, and undergoes disproportionation into the corresponding iminium 2+acy and enolate 2-acy . This is due to the excessive steric hindrance, which prevents electron-delocalization on the NCCO fragment, and thus, the capto-dative stabilization. This work suggests general guidelines for the design of highly persistent (amino)(carboxy)radicals, especially by emphasizing the key advantage of cyclic patterns.

Stable Di- and Tri-coordinated Carbon(II) Supported by an Electron-Rich β-Diketiminate Ligand

Complexes of the ubiquitous β-diketiminates (NacNac) ligands have been reported with most elements of the periodic table, including Group 14 Si, Ge, Sn, and Pb. The striking absence of carbon representatives has been attributed to the extreme electrophilicity of the putative C-NacNac adducts. An electron enriched 2,4-(dimethylamino)diketiminato backbone is described, which allowed for the synthesis and isolation of such stable pyrimidin-1,3-diium and pyrimidinium-2-ylidene salts. Structural and preliminary reactivity studies are reported, including an air-stable gold complex. An unforeseen original class of stable N-heterocyclic carbenes and, more generally, the potential of electron-rich NacNac patterns for taming highly electrophilic centers are showcased.

An air-persistent oxyallyl radical cation with simple di(methyl)amino substituents

We report an experimental and theoretical study of the 1,1,3,3-tetrakis-di(methylamino)oxyallyl radical cation. Despite simple substituents with minimal steric hindrance, this radical was found to be stable under an inert atmosphere and persistent for several hours in well-aerated solutions.

Tyrosine-1 of RNA Polymerase II CTD Controls Global Termination of Gene Transcription in Mammals

The carboxy-terminal domain (CTD) of RNA polymerase (Pol) II is composed of a repetition of YSPTSPS heptads and functions as a loading platform for protein complexes that regulate transcription, splicing, and maturation of RNAs. Here, we studied mammalian CTD mutants to analyze the function of tyrosine1 residues in the transcription cycle. Mutation of 3/4 of the tyrosine residues (YFFF mutant) resulted in a massive read-through transcription phenotype in the antisense direction of promoters as well as in the 3 direction several hundred kilobases downstream of genes. The YFFF mutant shows reduced Pol II at promoter-proximal pause sites, a loss of interaction with the Mediator and Integrator complexes, and impaired recruitment of these complexes to chromatin. Consistent with these observations, Pol II loading at enhancers and maturation of snRNAs are altered in the YFFF context genome-wide. We conclude that tyrosine1 residues of the CTD control termination of transcription by Pol II.

Investigation of the full reversal of selectivity in the reaction of aniline with 1,3-dichloro-1,3-bis(dimethylamino)vinamidinium salts

The addition of aniline, even in excess, to a solution of 1,3-dichloro-1,3-bis(dimethylamino)vinamidinium salt in the presence of triethylamine invariably leads to the formation of 2,4-bis(dimethylamino)quinoline. Conversely, delaying the addition of the base leads to the formation of 1,3-dimethylamino-N,N′-diphenylpropane-1,3-diimine, even when only a substoichiometric amount of aniline was used. A DFT study led to the consideration of factors that accounted for this reversal of reactivity. The role of a secondary orbital interaction in key transition states, as well as the role of solvent, is discussed.