Functional cooperation between CREM and GCNF directs gene expression in haploid male germ cells

Cellular differentiation and development of germ cells critically depend on a coordinated activation and repression of specific genes. The underlying regulation mechanisms, however, still lack a lot of understanding. Here, we describe that both the testis-specific transcriptional activator CREMτ (cAMP response element modulator tau) and the repressor GCNF (germ cell nuclear factor) have an overlapping binding site which alone is sufficient to direct cell type-specific expression in vivo in a heterologous promoter context. Expression of the transgene driven by the CREM/GCNF site is detectable in spermatids, but not in any somatic tissue or at any other stages during germ cell differentiation. CREMτ acts as an activator of gene transcription whereas GCNF suppresses this activity. Both factors compete for binding to the same DNA response element. Effective binding of CREM and GCNF highly depends on composition and epigenetic modification of the binding site. We also discovered that CREM and GCNF bind to each other via their DNA binding domains, indicating a complex interaction between the two factors. There are several testis-specific target genes that are regulated by CREM and GCNF in a reciprocal manner, showing a similar activation pattern as during spermatogenesis. Our data indicate that a single common binding site for CREM and GCNF is sufficient to specifically direct gene transcription in a tissue-, cell type- and differentiation-specific manner

Electrical transport studies of quench condensed Bi films at the initial stage of film growth: Structural transition and the possible formation of electron droplets

The electrical transport properties of amorphous Bi films prepared by sequential quench deposition have been studied in situ. A superconductor-insulator (S-I) transition was observed as the film was made increasingly thicker, consistent with previous studies. Unexpected behavior was found at the initial stage of film growth, a regime not explored in detail prior to the present work. As the temperature was lowered, a positive temperature coefficient of resistance (dR/dT > 0) emerged, with the resistance reaching a minimum before the dR/dT became negative again. This behavior was accompanied by a non-linear and asymmetric I-V characteristic. As the film became thicker, conventional variable-range hopping (VRH) was recovered. We attribute the observed crossover in the electrical transport properties to an amorphous to granular structural transition. The positive dR/dT found in the amorphous phase of Bi formed at the initial stage of film growth was qualitatively explained by the formation of metallic droplets within the electron glass.Comment: 7 pages, 6 figure

Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients

Bilaterality of breast cancer is an indicator of constitutional cancer susceptibility; however, the molecular causes underlying this predisposition in the majority of cases is not known. We hypothesize that epigenetic misregulation of cancer-related genes could partially account for this predisposition. We have performed methylation microarray analysis of peripheral blood DNA from 14 women with bilateral breast cancer compared with 14 unaffected matched controls throughout 17 candidate breast cancer susceptibility genes including BRCA1, BRCA2, CHEK2, ATM, ESR1, SFN, CDKN2A, TP53, GSTP1, CDH1, CDH13, HIC1, PGR, SFRP1, MLH1, RARB and HSD17B4. We show that the majority of methylation variability is associated with intragenic repetitive elements. Detailed validation of the tiled region around ATM was performed by bisulphite modification and pyrosequencing of the same samples and in a second set of peripheral blood DNA from 190 bilateral breast cancer patients compared with 190 controls. We show significant hypermethylation of one intragenic repetitive element in breast cancer cases compared with controls (P = 0.0017), with the highest quartile of methylation associated with a 3-fold increased risk of breast cancer (OR 3.20, 95% CI 1.78–5.86, P = 0.000083). Increased methylation of this locus is associated with lower steady-state ATM mRNA level and correlates with age of cancer patients but not controls, suggesting a combined age–phenotype-related association. This research demonstrates the potential for gene-body epigenetic misregulation of ATM and other cancer-related genes in peripheral blood DNA that may be useful as a novel marker to estimate breast cancer risk

The Polarised Valence Quark Distribution from semi-inclusive DIS

The semi-inclusive difference asymmetry A^{h^{+}-h^{-}} for hadrons of opposite charge has been measured by the COMPASS experiment at CERN. The data were collected in the years 2002-2004 using a 160 GeV polarised muon beam scattered off a large polarised ^6LiD target and cover the range 0.006 < x < 0.7 and 1 < Q^2 < 100 (GeV/c)^2. In leading order QCD (LO) the asymmetry A_d^{h^{+}-h^{-}} measures the valence quark polarisation and provides an evaluation of the first moment of Delta u_v + Delta d_v which is found to be equal to 0.40 +- 0.07 (stat.) +- 0.05 (syst.) over the measured range of x at Q^2 = 10 (GeV/c)^2. When combined with the first moment of g_1^d previously measured on the same data, this result favours a non-symmetric polarisation of light quarks Delta u-bar = - Delta d-bar at a confidence level of two standard deviations, in contrast to the often assumed symmetric scenario Delta u-bar = Delta d-bar = Delta s-bar = Delta s.Comment: 7 pages, 3 figures, COMPASS, revised: details added, author list update

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.Peer reviewe