Exploring cellular memory molecules marking competent and active transcriptions

<p>Abstract</p> <p>Background</p> <p>Development in higher eukaryotes involves programmed gene expression. Cell type-specific gene expression is established during this process and is inherited in succeeding cell cycles. Higher eukaryotes have evolved elegant mechanisms by which committed gene-expression states are transmitted through numerous cell divisions. Previous studies have shown that both DNase I-sensitive sites and the basal transcription factor TFIID remain on silenced mitotic chromosomes, suggesting that certain trans-factors might act as bookmarks, maintaining the information and transmitting it to the next generation.</p> <p>Results</p> <p>We used the mouse globin gene clusters as a model system to examine the retention of active information on M-phase chromosomes and its contribution to the persistence of transcriptional competence of these gene clusters in murine erythroleukemia cells. In cells arrested in mitosis, the erythroid-specific activator NF-E2p45 remained associated with its binding sites on the globin gene loci, while the other major erythroid factor, GATA-1, was removed from chromosome. Moreover, despite mitotic chromatin condensation, the distant regulatory regions and promoters of transcriptionally competent globin gene loci are marked by a preserved histone code consisting in active histone modifications such as H3 acetylation, H3-K4 dimethylation and K79 dimethylation. Further analysis showed that other active genes are also locally marked by the preserved active histone code throughout mitotic inactivation of transcription.</p> <p>Conclusion</p> <p>Our results imply that certain kinds of specific protein factors and active histone modifications function as cellular memory markers for both competent and active genes during mitosis, and serve as a reactivated core for the resumption of transcription when the cells exit mitosis.</p

Association of smoking, alcohol drinking and dietary factors with esophageal cancer in high- and low-risk areas of Jiangsu Province, China

To study the main environmental and lifestyle factors that account for the regional differences in esophageal cancer (EC) risk in low- and high-risk areas of Jiangsu Province, China. Since 2003, a population-based casecontrol study has been conducted simultaneously in lowrisk (Ganyu County) and high-risk (Dafeng County) areas of Jiangsu Province, China. Using identical protocols and pre-tested standardized questionnaire, following written informed consent, eligible subjects were inquired about their detail information on potential determinants of EC, including demographic information, socio-economic status, living conditions, disease history, family cancer history, smoking, alcohol drinking, dietary habits, frequency, amount of food intake, etc. Conditional logistic regression with maximum likelihood estimation was used to obtain Odds ratio (OR) and 95 % confi dence interval (95% CI), after adjustment for potential confounders In the preliminary analysis of the ongoing study, we recruited 291 pairs of cases and controls in Dafeng and 240 pairs of cases and controls in Ganyu, respectively. In both low-risk and high-risk areas, EC was inversely associated with socio-economic status, such as level of education, past economic status and body mass index. However, this disease was more frequent among those who had a family history of cancer or encountered misfortune in the past 10 years. EC was also more frequent among smokers, alcohol drinkers and fast eaters. Furthermore, there was a geographic variation of the associations between smoking, alcohol drinking and EC risk despite the similar prevalence of these risk factors in both low-risk and high-risk areas. The dose-response relationship of smoking and smoking related variables, such as age of the fi rst smoking, duration and amount were apparent only in high-risk areas. On the contrary, a dose-response relationship on the effect of alcohol drinking on EC was observed only in low-risk area

NR4A Receptors Differentially Regulate NF-κB Signaling in Myeloid Cells

Dysregulation of inflammatory responses is a hallmark of multiple diseases such as atherosclerosis and rheumatoid arthritis. As constitutively active transcription factors, NR4A nuclear receptors function to control the magnitude of inflammatory responses and in chronic inflammatory disease can be protective or pathogenic. Within this study, we demonstrate that TLR4 stimulation using the endotoxin lipopolysaccharide (LPS) rapidly enhances NR4A1–3 expression in human and murine, primary and immortalized myeloid cells with concomitant gene transcription and protein secretion of MIP-3α, a central chemokine implicated in numerous pathologies. Deficiency of NR4A2 and NR4A3 in human and murine myeloid cells reveals that both receptors function as positive regulators of enhanced MIP-3α expression. In contrast, within the same cell types and conditions, altered NR4A activity leads to suppression of LPS-induced MCP-1 gene and protein expression. An equivalent pattern of inflammatory gene regulation is replicated in TNFα-treated myeloid cells. We show that NF-κB is the critical regulator of NR4A1–3, MIP-3α, and MCP-1 during TLR4 stimulation in myeloid cells and highlight a parallel mechanism whereby NR4A activity can repress or enhance NF-κB target gene expression simultaneously. Mechanistic insight reveals that NR4A2 does not require DNA-binding capacity in order to enhance or repress NF-κB target gene expression simultaneously and establishes a role for NF-κB family member Relb as a novel NR4A target gene involved in the positive regulation of MIP-3α. Thus, our data reveal a dynamic role for NR4A receptors concurrently enhancing and repressing NF-κB activity in myeloid cells leading to altered transcription of key inflammatory mediators

Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy

The histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability. Interestingly, we found c-Myc was a key downstream effector of the USP1-KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC

Piecing Together the X-ray Background: Bolometric Corrections for Active Galactic Nuclei

(Abridged) The X-ray background can be used to constrain the accretion history of Supermassive Black Holes (SMBHs) in Active Galactic Nuclei (AGN). A knowledge of the hard X-ray bolometric correction, \kappa_{2-10keV} is a vital input into these studies. Variations in the disk emission in the UV have not previously been taken into account in calculating \kappa_{2-10keV}; we show that such variations are important by constructing optical--to--X-ray SEDs for 54 AGN. In particular, we use FUSE UV and X-ray data from the literature to constrain the disk emission as well as possible. Previous work has suggested a dependence of \kappa_{2-10keV} on AGN luminosity, but we find significant spread in \kappa_{2-10keV} with no simple dependence on luminosity. Populations such as Narrow-Line Seyfert 1 nuclei (NLS1s), Radio Loud and X-ray Weak AGN may have values of \kappa_{2-10keV} differing systematically from the rest of the AGN population. Other sources of uncertainty include intrinsic extinction in the optical--UV, X-ray and UV variability and uncertainties in SMBH mass estimates. Our results suggest a more well-defined relationship between \kappa_{2-10keV} and Eddington ratio in AGN, with a transitional region at an Eddington ratio of ~0.1, below which the bolometric correction is typically 15 - 25, and above which it is typically 40 - 70. We consider the potential implied parallels with the low/hard and high/soft states in Galactic Black Hole (GBH) accretion, and present bolometric corrections for the GBH binary GX 339-4 for comparison. Our findings reinforce previous studies proposing a multi-state description of AGN accretion analogous to that for GBH binaries. Future calculations of the SMBH mass density may need to account for the possible dependence of \kappa_{2-10keV} on Eddington ratio.Comment: 19 pages, 16 figures, 3 tables. Accepted for publication in MNRA

Implicator-conjunctor based models of fuzzy rough sets: definitions and properties

Ever since the first hybrid fuzzy rough set model was proposed in the early 1990' s, many researchers have focused on the definition of the lower and upper approximation of a fuzzy set by means of a fuzzy relation. In this paper, we review those proposals which generalize the logical connectives and quantifiers present in the rough set approximations by means of corresponding fuzzy logic operations. We introduce a general model which encapsulates all of these proposals, evaluate it w.r.t. a number of desirable properties, and refine the existing axiomatic approach to characterize lower and upper approximation operators