Geometric Characteristics of Dynamic Correlations for Combinatorial Regulation in Gene Expression Noise

Knowing which mode of combinatorial regulation (typically, AND or OR logic operation) that a gene employs is important for determining its function in regulatory networks. Here, we introduce a dynamic cross-correlation function between the output of a gene and its upstream regulator concentrations for signatures of combinatorial regulation in gene expression noise. We find that the correlation function is always upwards convex for the AND operation whereas downwards convex for the OR operation, whichever sources of noise (intrinsic or extrinsic or both). In turn, this fact implies a means for inferring regulatory synergies from available experimental data. The extensions and applications are discussed.Comment: 4 pages, 3 figures, and supporting materia

Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells

Cytoplasmic chromatin triggers inflammation in senescence and cancer

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders

Synchronization and clustering of synthetic genetic networks: A role for cis-regulatory modules

The effect of signal integration through cis-regulatory modules (CRMs) on synchronization and clustering of populations of two-component genetic oscillators coupled by quorum sensing is in detail investigated. We find that the CRMs play an important role in achieving synchronization and clustering. For this, we investigate 6 possible cis-regulatory input functions (CRIFs) with AND, OR, ANDN, ORN, XOR, and EQU types of responses in two possible kinds of cell-to-cell communications: activator-regulated communication (i.e., the autoinducer regulates the activator) and repressor-regulated communication (i.e., the autoinducer regulates the repressor). Both theoretical analysis and numerical simulation show that different CRMs drive fundamentally different cellular patterns, such as complete synchronization, various cluster-balanced states and several cluster-nonbalanced states.Comment: 30 pages, 8 figure

Comparing Brane Inflation to WMAP

We compare the simplest realistic brane inflationary model to recent cosmological data, including WMAP 3-year cosmic microwave background (CMB) results, Sloan Digital Sky Survey luminous red galaxies (SDSS LRG) power spectrum data and Supernovae Legacy Survey (SNLS) Type 1a supernovae distance measures. Here, the inflaton is simply the position of a $D3$-brane which is moving towards a $\bar{D}3$-brane sitting at the bottom of a throat (a warped, deformed conifold) in the flux compactified bulk in Type IIB string theory. The analysis includes both the usual slow-roll scenario and the Dirac-Born-Infeld scenario of slow but relativistic rolling. Requiring that the throat is inside the bulk greatly restricts the allowed parameter space. We discuss possible scenarios in which large tensor mode and/or non-Gaussianity may emerge. Here, the properties of a large tensor mode deviate from that in the usual slow-roll scenario, providing a possible stringy signature. Overall, within the brane inflationary scenario, the cosmological data is providing information about the properties of the compactification of the extra dimensions.Comment: 45 pages 11 figure

Duality Cascade in Brane Inflation

We show that brane inflation is very sensitive to tiny sharp features in extra dimensions, including those in the potential and in the warp factor. This can show up as observational signatures in the power spectrum and/or non-Gaussianities of the cosmic microwave background radiation (CMBR). One general example of such sharp features is a succession of small steps in a warped throat, caused by Seiberg duality cascade using gauge/gravity duality. We study the cosmological observational consequences of these steps in brane inflation. Since the steps come in a series, the prediction of other steps and their properties can be tested by future data and analysis. It is also possible that the steps are too close to be resolved in the power spectrum, in which case they may show up only in the non-Gaussianity of the CMB temperature fluctuations and/or EE polarization. We study two cases. In the slow-roll scenario where steps appear in the inflaton potential, the sensitivity of brane inflation to the height and width of the steps is increased by several orders of magnitude comparing to that in previously studied large field models. In the IR DBI scenario where steps appear in the warp factor, we find that the glitches in the power spectrum caused by these sharp features are generally small or even unobservable, but associated distinctive non-Gaussianity can be large. Together with its large negative running of the power spectrum index, this scenario clearly illustrates how rich and different a brane inflationary scenario can be when compared to generic slow-roll inflation. Such distinctive stringy features may provide a powerful probe of superstring theory.Comment: Corrections in Eq.(5.47), Eq (5.48), Eq(5.49) and Fig

Challenges in QCD matter physics - The Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sqrt(s_NN) = 2.7 - 4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (mu_B > 500 MeV), effects of chiral symmetry, and the equation-of-state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2022, in the context of the worldwide efforts to explore high-density QCD matter.Comment: 15 pages, 11 figures. Published in European Physical Journal

Identification of a Functional Genetic Variant at 16q12.1 for Breast Cancer Risk: Results from the Asia Breast Cancer Consortium

Genetic factors play an important role in the etiology of breast cancer. We carried out a multi-stage genome-wide association (GWA) study in over 28,000 cases and controls recruited from 12 studies conducted in Asian and European American women to identify genetic susceptibility loci for breast cancer. After analyzing 684,457 SNPs in 2,073 cases and 2,084 controls in Chinese women, we evaluated 53 SNPs for fast-track replication in an independent set of 4,425 cases and 1,915 controls of Chinese origin. Four replicated SNPs were further investigated in an independent set of 6,173 cases and 6,340 controls from seven other studies conducted in Asian women. SNP rs4784227 was consistently associated with breast cancer risk across all studies with adjusted odds ratios (95% confidence intervals) of 1.25 (1.20−1.31) per allele (P = 3.2×10−25) in the pooled analysis of samples from all Asian samples. This SNP was also associated with breast cancer risk among European Americans (per allele OR  = 1.19, 95% CI  = 1.09−1.31, P = 1.3×10−4, 2,797 cases and 2,662 controls). SNP rs4784227 is located at 16q12.1, a region identified previously for breast cancer risk among Europeans. The association of this SNP with breast cancer risk remained highly statistically significant in Asians after adjusting for previously-reported SNPs in this region. In vitro experiments using both luciferase reporter and electrophoretic mobility shift assays demonstrated functional significance of this SNP. These results provide strong evidence implicating rs4784227 as a functional causal variant for breast cancer in the locus 16q12.1 and demonstrate the utility of conducting genetic association studies in populations with different genetic architectures

Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10−12 in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85–0.94) and 0.80 (0.75–0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10−6 from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10−7), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk