CARM1 and BAF155: an example of how chromatin remodeling factors can be relocalized and contribute to cancer

In a recent article, Wang and colleagues reported the discovery of a mechanism by which CARM1 regulates the genomic localization of BAF155 (a SWI/SNF subunit involved in chromatin remodeling) through post-translational methylation at R1064 arginine residues. This modification leads to the relocalization of BAF155-containing SWI/SNF complexes to regions containing genes involved in the Myc oncogenic pathway. The results presented are evidence that these interactions constitute a mechanism by which the BAF155 chromatin remodeling factor contributes to cancer

Fiscal-capacity equalization-grants with taxpayers' lobbying

The economic analysis of tax-base equalization-grants from central to local governments suggests that the transfer mechanism distorts fiscal policies by providing incentives to local governments to set excessively high tax rates. In this paper, we extend the analysis by allowing taxpayers to lobby the policy makers for reductions of their own tax burdens. In principle, the distortions spurring from the lobbying activity should mitigate those caused by the equalization program. In contrast, we show that taxpayers lobbying amplifi es the distortions of the equalization mechanism. The degree of fiscal equalization can then be adjusted to alleviate the efficiency costs of lobbying

La secreción biliar en conejos anestesiados: probable irrelevancia del control nervioso vagal

Sorne aspects of the vagal control of the biliary secretion in anaesthetized rabbits have been investigated. Neither the cut nor the stimulation of the vagus nerves in the neck or abdomen induced significant changes either on bile. flow or in its bile salts and chloride composition. Adrenaline reduced and "Priscol" increased the biliary flow. The present results seem to indicate a lack of efficacy of the vagus in order either to keep a basal bile flow or to increase it in response to specific stimuli. This physiological inefficacy, although could be explained by adrenergic inhibition, may be ought to the high basal flow of this species and the very low concentrating ability of its gallbladder.Se han investigado algunos aspectos del control vagal de la secreción biliar en conejos anestesiados. Ni el corte ni la estimulación de los nervios vagos en cuello o abdomen indujeron cambios significativos en el flujo de bilis ni en su composición en sales biliares y cloruros. La adrenalina redujo y el "Priscol" aumentó el flujo biliar. Los presentes resultados parecen indicar una falta de eficacia de los vagos para mantener un fluj o basal de bilis o para incrementarlo en r,espuesta a estímulos específicos. Esta ineficacia fisíológica, si bien podría explicarse en parte por inhibición adrenérgica, puede deberse al elevado flujo basal de esta especie y a la escasa capacidad concentradora de su vesícula biliar

La secreción biliar en conejos anestesiados: probable irrelevancia del control nervioso vagal

Se han investigado algunos aspectos del control vagal de la secreción biliar en conejos anestesiados. Ni el corte ni la estimulación de los nervios vagos en cuello o abdomen indujeron cambios significativos en el flujo de bilis ni en su composición en sales biliares y cloruros. La adrenalina redujo y el "Priscol" aumentó el flujo biliar. Los presentes resultados parecen indicar una falta de eficacia de los vagos para mantener un flujo basal de bilis o para incrementarlo en r,espuesta a estímulos específicos. Esta ineficacia fisíológica, si bien podría explicarse en parte por inhibición adrenérgica, puede deberse al elevado flujo basal de esta especie y a la escasa capacidad concentradora de su vesícula biliar.Some aspects of the vagal control of the biliary secretion in anaesthetized rabbits have been investigated. Neither the cut nor the stimulation of the vagus nerves in the neck or abdomen induced significant changes either on bile. flow or in its bile salts and chloride ,composition. Adrenaline reduced and "Priscol" increased the biliary flow. The present results seem to indicate a lack of effi cacy of the vagus in order either to keep a basal bile flow or to increase it in response to specific stimuli. This physiological inefficacy, although could be explaíned by adrenergic inhibition, may be ought to the high basal flow of this species and the very low concentrating ability oí its gallbladder

Differential DNA methylation profiles in gynecological cancers and correlation with clinico-pathological data

BACKGROUND: Epigenetic gene silencing is one of the major causes of carcinogenesis. Its widespread occurrence in cancer genome could inactivate many cellular pathways including DNA repair, cell cycle control, apoptosis, cell adherence, and detoxification. The abnormal promoter methylation might be a potential molecular marker for cancer management. METHODS: For rapid identification of potential targets for aberrant methylation in gynecological cancers, methylation status of the CpG islands of 34 genes was determined using pooled DNA approach and methylation-specific PCR. Pooled DNA mixture from each cancer type (50 cervical cancers, 50 endometrial cancers and 50 ovarian cancers) was made to form three test samples. The corresponding normal DNA from the patients of each cancer type was also pooled to form the other three control samples. Methylated alleles detected in tumors, but not in normal controls, were indicative of aberrant methylation in tumors. Having identified potential markers, frequencies of methylation were further analyzed in individual samples. Markers identified are used to correlate with clinico-pathological data of tumors using χ(2 )or Fisher's exact test. RESULTS: APC and p16 were hypermethylated across the three cancers. MINT31 and PTEN were hypermethylated in cervical and ovarian cancers. Specific methylation was found in cervical cancer (including CDH1, DAPK, MGMT and MINT2), endometrial cancer (CASP8, CDH13, hMLH1 and p73), and ovarian cancer (BRCA1, p14, p15, RIZ1 and TMS1). The frequencies of occurrence of hypermethylation in 4 candidate genes in individual samples of each cancer type (DAPK, MGMT, p16 and PTEN in 127 cervical cancers; APC, CDH13, hMLH1 and p16 in 60 endometrial cancers; and BRCA1, p14, p16 and PTEN in 49 ovarian cancers) were examined for further confirmation. Incidence varied among different genes and in different cancer types ranging from the lowest 8.2% (PTEN in ovarian cancer) to the highest 56.7% (DAPK in cervical cancer). Aberrant methylation for some genes (BRCA1, DAPK, hMLH1, MGMT, p14, p16, and PTEN) was also associated with clinico-pathological data. CONCLUSION: Thus, differential methylation profiles occur in the three types of gynecologic cancer. Detection of methylation for critical loci is potentially useful as epigenetic markers in tumor classification. More studies using a much larger sample size are needed to define the potential role of DNA methylation as marker for cancer management

Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis

Epithelial-mesenchymal (EMT) and mesenchymal-epithelial (MET) transitions occur in the development of human tumorigenesis and are part of the natural history of the process to adapt to the changing microenvironment. In this setting, the miR-200 family is recognized as a master regulator of the epithelial phenotype by targeting ZEB1 and ZEB2, two important transcriptional repressors of the cell adherence (E-cadherin) and polarity (CRB3 and LGL2) genes. Recently, the putative DNA methylation associated inactivation of various miR-200 members has been described in cancer. Herein, we show that the miR-200ba429 and miR-200c141 transcripts undergo a dynamic epigenetic regulation linked to EMT or MET phenotypes in tumor progression. The 5′-CpG islands of both miR-200 loci were found unmethylated and coupled to the expression of the corresponding miRNAs in human cancer cell lines with epithelial features, such as low levels of ZEB1/ZEB2 and high expression of E-cadherin, CRB3 and LGL2, while CpG island hypermethylation-associated silencing was observed in transformed cells with mesenchymal characteristics. The recovery of miR-200ba429 and miR-200c141 expression by stable transfection in the hypermethylated cells restored the epithelial markers and inhibited migration in cell culture and tumoral growth and metastasis formation in nude mice. We also discovered, using both cell culture and animal models, that the miR-200 epigenetic silencing is not an static and fixed process but it can be shifted to hypermethylated or unmethylated 5′-CpG island status corresponding to the EMT and MET phenotypes, respectively. In fact, careful laser microdissection in human primary colorectal tumorigenesis unveiled that in normal colon mucosa crypts (epithelia) and stroma (mesenchyma) already are unmethylated and methylated at these loci, respectively; and that the colorectal tumors undergo selective miR-200 hypermethylation of their epithelial component. These findings indicate that the epigenetic silencing plasticity of the miR-200 family contributes to the evolving and adapting phenotypes of human tumors

The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors

13 pages, 7 figures.Transcriptional repression mechanisms have emerged as one of the crucial processes for the downregulation of E-cadherin expression during development and tumour progression. Recently, several E-cadherin transcriptional repressors have been characterized (Snail, E12/E47, ZEB-1 and SIP-1) and shown to act through an interaction with proximal E-boxes of the E-cadherin promoter. We have analyzed the participation of another member of the Snail family, Slug, and observed that it also behaves as a repressor of E-cadherin expression. Stable expression of Slug in MDCK cells leads to the full repression of E-cadherin at transcriptional level and triggers a complete epithelial to mesenchymal transition. Slug-induced repression of E-cadherin is mediated by its binding to proximal E-boxes, particularly to the E-pal element of the mouse promoter. Detailed analysis of the binding affinity of different repressors to the E-pal element indicates that Slug binds with lower affinity than Snail and E47 proteins. These results, together with the known expression patterns of these factors in embryonic development and carcinoma cell lines, support the idea that the in vivo action of the different factors in E-cadherin repression can be modulated by their relative concentrations as well as by specific cellular or tumour contexts.This work was supported by the Spanish Ministry of Science and Technology (SAF2001-2819), Instituto de Salud Carlos III (FIS01/1174) and the Comunidad Autónoma de Madrid (08.1/0055./2000). V.B. has been funded by predoctoral fellowships from the Fundación Científica de la Asociación Española contra el Cáncer (AECC) and Instituto de Salud Carlos III. H.P. is a predoctoral fellow of the Spanish Ministry of Education, Culture and Sports.Peer reviewe

Taxing high income earners: tax avoidance and mobility

The taxation of high-income earners is of importance to every country and is the subject of a considerable amount of recent academic research. Such high-income earners contribute substantial amounts of tax and generate significant positive spillovers, but are also highly mobile: a 1% increase in the top marginal income tax rate increases out-migrations by around 1.5 to 3%. We review research into taxation of high-income earners to provide a synthesis of existing theoretical and empirical understanding. We offer various avenues for potential future theoretical and empirical research

NuRD-dependent DNA methylation prevents ES cells from accessing a trophectoderm fate

Embryonic Stem (ES) cells are able to give rise to the three germ layers of the embryo but are prevented from contributing to the trophoblast. The molecular nature of this barrier between embryonic and trophectodermal cell fates is not clear, but is known to involve DNA methylation. Here we demonstrate that the Nucleosome Remodeling and Deacetylation (NuRD) co-repressor complex maintains the developmental barrier between embryonic and trophectodermal cell fates by maintaining transcriptional silencing of trophectoderm determinant genes in ES cells. We further show that NuRD activity facilitates DNA methylation of several of its target promoters, where it acts non-redundantly with DNA methylation to enforce transcriptional silencing. NuRD-deficient ES cells fail to completely silence expression of the trophectoderm determinant genes Elf5 and Eomes, but this alone is not sufficient to induce transdifferentiation towards the trophectoderm fate. Rather this leaves ES cells capable of activating expression of trophectoderm-specific genes in response to appropriate extracellular signals, enabling them to commit to a trophectodermal cell fate. Our findings clarify the molecular nature of the developmental barrier between the embryonic and trophoblast cell fates, and establish a role for NuRD activity in specifying sites for de novo DNA methylation. (C) 2012. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0)

The affinity of different MBD proteins for a specific methylated locus depends on their intrinsic binding properties

The methyl-CpG binding domain (MBD) family of proteins was defined based on sequence similarity in their DNA binding domains. In light of their high degree of conservation, it is of inherent interest to determine the genomic distribution of these proteins, and their associated co-repressor complexes. One potential determinant of specificity resides in differences in the intrinsic DNA binding properties of the various MBD proteins. In this report, we use a capillary electrophoretic mobility shift assay (CEMSA) with laser-induced fluorescence (LIF) and neutral capillaries to calculate MBD-DNA binding affinities. MBD proteins were assayed on pairs of methylated and unmethylated duplex oligos corresponding to the promoter regions of the BRCA1, MLH1, GSTP1 and p16(INK4a) genes, and binding affinities for each case were calculated by Scatchard analyses. With the exception of mammalian MBD3 and Xenopus MBD3 LF, all the MBD proteins showed higher affinity for methylated DNA (in the nanomolar range) than for unmethylated DNA (in the micromolar range). Significant differences between MBD proteins in the affinity for methylated DNA were observed, ranging within two orders of magnitude. By mutational analysis of MBD3 and using CEMSA, we demonstrate the critical role of specific residues within the MBD in conferring selectivity for methylated DNA. Interestingly, the binding affinity of specific MBD proteins for methylated DNA fragments from naturally occurring sequences are affected by local methyl-CpG spacing