A dinucleotide deletion in the ankyrin promoter alters gene expression, transcription initiation and TFIID complex formation in hereditary spherocytosis

Ankyrin defects are the most common cause of hereditary spherocytosis (HS). In some HS patients, mutations in the ankyrin promoter have been hypothesized to lead to decreased ankyrin mRNA synthesis. The ankyrin erythroid promoter is a member of the most common class of mammalian promoters which lack conserved TATA, initiator or other promoter cis elements and have high G+C content, functional Sp1 binding sites and multiple transcription initiation sites. We identified a novel ankyrin gene promoter mutation, a TG deletion adjacent to a transcription initiation site, in a patient with ankyrin-linked HS and analyzed its effects on ankyrin expression. In vitro, the mutant promoter directed decreased levels of gene expression, altered transcription initiation site utilization and exhibited defective binding of TATA-binding protein (TBP) and TFIID complex formation. In a transgenic mouse model, the mutant ankyrin promoter led to abnormalities in gene expression, including decreased expression of a reporter gene and altered transcription initiation site utilization. These data indicate that the mutation alters ankyrin gene transcription and contributes to the HS phenotype by decreasing ankyrin gene synthesis via disruption of TFIID complex interactions with the ankyrin core promoter. These studies support the model that in promoters that lack conserved cis elements, the TFIID complex directs preinitiation complex formation at specific sites in core promoter DNA and provide the first evidence that disruption of TBP binding and TFIID complex formation in this type of promoter leads to alterations in start site utilization, decreased gene expression and a disease phenotype in viv

A dinucleotide deletion in the ankyrin promoter alters gene expression, transcription initiation and TFIID complex formation in hereditary spherocytosis

Ankyrin defects are the most common cause of hereditary spherocytosis (HS). In some HS patients, mutations in the ankyrin promoter have been hypothesized to lead to decreased ankyrin mRNA synthesis. The ankyrin erythroid promoter is a member of the most common class of mammalian promoters which lack conserved TATA, initiator or other promoter cis elements and have high G+C content, functional Sp1 binding sites and multiple transcription initiation sites. We identified a novel ankyrin gene promoter mutation, a TG deletion adjacent to a transcription initiation site, in a patient with ankyrin-linked HS and analyzed its effects on ankyrin expression. In vitro, the mutant promoter directed decreased levels of gene expression, altered transcription initiation site utilization and exhibited defective binding of TATA-binding protein (TBP) and TFIID complex formation. In a transgenic mouse model, the mutant ankyrin promoter led to abnormalities in gene expression, including decreased expression of a reporter gene and altered transcription initiation site utilization. These data indicate that the mutation alters ankyrin gene transcription and contributes to the HS phenotype by decreasing ankyrin gene synthesis via disruption of TFIID complex interactions with the ankyrin core promoter. These studies support the model that in promoters that lack conserved cis elements, the TFIID complex directs preinitiation complex formation at specific sites in core promoter DNA and provide the first evidence that disruption of TBP binding and TFIID complex formation in this type of promoter leads to alterations in start site utilization, decreased gene expression and a disease phenotype in viv

Search for pair-produced vector-like B quarks in proton-proton collisions at s\sqrt{s} = 8 TeV

A search for the production of a heavy B quark, having electric charge -1/3 and vector couplings to W, Z, and H bosons, is carried out using proton-proton collision data recorded at the CERN LHC by the CMS experiment, corresponding to an integrated luminosity of 19.7 inverse femtobarns. The B quark is assumed to be pair-produced and to decay in one of three ways: to tW, bZ, or bH. The search is carried out in final states with one, two, and more than two charged leptons, as well as in fully hadronic final states. Each of the channels in the exclusive final-state topologies is designed to be sensitive to specific combinations of the B quark-antiquark pair decays. The observed event yields are found to be consistent with the standard model expectations in all the final states studied. A statistical combination of these results is performed and upper limits are set on the cross section of the strongly produced B quark-antiquark pairs as a function of the B quark mass. Lower limits on the B quark mass between 740 and 900 GeV are set at a 95% confidence level, depending on the values of the branching fractions of the B quark to tW, bZ, and bH. Overall, these limits are the most stringent to date

Search for supersymmetry with photons in pp collisions at s\sqrt s = 8 TeV

Two searches for physics beyond the standard model in events containing photons are presented. The data sample used corresponds to an integrated luminosity of 19.7 inverse femtobarns of proton-proton collisions at $\sqrt{s}$ = 8 TeV, collected with the CMS experiment at the CERN LHC. The analyses pursue different inclusive search strategies. One analysis requires at least one photon, at least two jets, and a large amount of transverse momentum imbalance, while the other selects events with at least two photons and at least one jet, and uses the razor variables to search for signal events. The background expected from standard model processes is evaluated mainly from data. The results are interpreted in the context of general gauge-mediated supersymmetry, with the next-to-lightest supersymmetric particle either a bino- or wino-like neutralino, and within simplified model scenarios. Upper limits at 95% confidence level are obtained for cross sections as functions of the masses of the intermediate supersymmetric particles