FOXE1 regulates migration and invasion in thyroid cancer cells and targets ZEB1

FOXE1 is a thyroid-specific transcription factor essential for thyroid gland development and maintenance of the differentiated state. Interestingly, a strong association has been recently described between FOXE1 expression and susceptibility to thyroid cancer, but little is known about the mechanisms underlying FOXE1-induced thyroid tumorigenesis. Here, we used a panel of human thyroid cancer-derived cell line s covering the spectrum of thyroid cancer phenotypes to examine FOXE1 expression and to test for correlations between FOXE1 expression, the allele frequency of two SNPs and a length polymorphism in or near the FOXE1 locus associated with cancer susceptibility, and the migration ability of thyroid cancer cell lines. Results showed that FOXE1 expression correlated with differentiation status according to histological sub-type, but not with SNP genotype or cell migration ability. However, loss-and-gain-of-function experiments revealed that FOXE1 modulates cell migration, suggesting a role in epithelial-to-mesenchymal transition (EMT). Our previous genome-wide expression analysis identified Zeb1, a major EMT inducer, as a putative Foxe1 target gene. Indeed, gene silencing of FOXE1 decreased ZEB1 expression, whereas its overexpression increased ZEB1 transcriptional activity. FOXE1 was found to directly interact with the ZEB1 promoter. Lastly, ZEB1 silencing decreased the ability of thyroid tumoral cells to migrate and invade, pointing to its im portance in thyroid tumor mestastases. In conclusion, we have identified ZEB1 as a bona fide target of FOXE1 in thyroid cancer cells, which provides new insights into the role of FOXE1 in regulating cell migration and invasion in thyroid cancerThis work was supported by grants SAF2016-75531-R from Ministerio de Ciencia, Innovación y Universidades (MICIU), Spain, Fondo Europeo de Desarrollo Regional FEDER, B2017/BMD-3724 from Comunidad de Madrid, and GCB14142311CRES from Fundación Española Contra el Cáncer (AECC)

Ultrafast excited state dynamics of silver ion-mediated cytosine–cytosine base pairs in metallo-DNA

The following article appeared in The Journal of Chemical Physics 153.10 (2020): 105104 and may be found at ttps://doi.org/10.1063/5.0020463To better understand the nexus between structure and photophysics in metallo-DNA assemblies, the parallel-stranded duplex formed by the all-cytosine oligonucleotide, dC20, and silver nitrate was studied by circular dichroism (CD), femtosecond transient absorption spectroscopy, and time-dependent-density functional theory calculations. Silver(I) ions mediate Cytosine–Cytosine (CC) base pairs by coordinating to the N3 atoms of two cytosines. Although these silver(I) mediated CC base pairs resemble the proton-mediated CC base pairs found in i-motif DNA at first glance, a comparison of experimental and calculated CD spectra reveals that silver ion-mediated i-motif structures do not form. Instead, the parallel-stranded duplex formed between dC20 and silver ions is proposed to contain consecutive silver-mediated base pairs with high propeller twist-like ones seen in a recent crystal structure of an emissive, DNA-templated silver cluster. Femtosecond transient absorption measurements with broadband probing from the near UV to the near IR reveal an unusually long-lived (>10 ns) excited state in the dC20 silver ion complex that is not seen in dC20 in single-stranded or i-motif forms. This state is also absent in a concentrated solution of cytosine–silver ion complexes that are thought to assemble into planar ribbons or sheets that lack stacked silver(I) mediated CC base pairs. The large propeller twist angle present in metal-mediated base pairs may promote the formation of long-lived charged separated or triplet states in this metallo-DNAThe work at The Ohio State University was supported by a grant from the U.S. National Science Foundation (Grant No. CHE1800471). L.M.-F. thanks the MINECO project (No. CTQ2016- 76061-P) for financial support and the Centro de Computación Científica, CCC-UAM, for generous allocation of computational time. The authors declare no competing financial interes

New insights into FoxE1 functions: identification of direct FoxE1 targets in thyroid cells

This is an open-access article distributed under the terms of the Creative Commons Attribution License.[Background]: FoxE1 is a thyroid-specific forkhead transcription factor essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in adults. FoxE1 recognizes and binds to a short DNA sequence present in thyroglobulin (Tg) and thyroperoxidase (Tpo) promoters, but FoxE1 binding to regulatory regions other than Tg and Tpo promoters remains almost unexplored. Improving knowledge of the regulatory functions of FoxE1 is necessary to clarify its role in endocrine syndromes and cancer susceptibility. [Methodology/Principal Finding]:I n order to further investigate downstream FoxE1 targets, we performed a genome-wide expression screening after knocking-down FoxE1 and obtained new insights into FoxE1 transcriptional networks in thyroid follicular cells. After validation, we confirmed Adamts9, Cdh1, Duox2 and S100a4 as upregulated genes and Casp4, Creld2, Dusp5, Etv5, Hsp5a, Nr4a2 and Tm4sf1 as downregulated genes when FoxE1 was silenced. In promoter regions of putative FoxE1-regulated genes and also in the promoters of the classical thyroid genes Nis, Pax8 and Titf1, we performed an in silico search of the FoxE1 binding motif that was in close proximity to the NF1/CTF binding sequence, as previously described for other forkhead factors. Using chromatin immunoprecipitation we detected specific in vivo FoxE1 binding to novel regulatory regions in two relevant thyroid genes, Nis and Duox2. Moreover, we demonstrated simultaneous binding of FoxE1 and NF1/CTF to the Nis upstream enhancer region, as well as a clear functional activation of the Nis promoter by both transcription factors. [Conclusions/Significance]:In search for potential downstream mediators of FoxE1 function in thyroid cells, we identified two novel direct FoxE1 target genes. To our knowledge, this is the first evidence regarding the implication of Nis and Duox2 in executing the transcriptional program triggered by FoxE1. Furthermore, this study points out the important role of FoxE1 in the regulation of a large number of genes in thyroid cells. © 2013 Fernández et al.This work was supported by Grants BFU-2010-16025 from the Dirección General de Proyectos de Investigación; RD06/0020/0060 and RD12/0036/0030 from FIS, Instituto de Salud Carlos III; and S2011/BMD-2328 TIRONET project from the Comunidad de Madrid (Spain). LP Fernández holds a postdoctoral grant of the Juan de la Cierva programme of the Spanish Government.Peer Reviewe

Identification of genomic regions regulating sex determination in Atlantic salmon using high density SNP data

Background: A complete understanding of the genetic basis for sexual determination and differentiation is necessary in order to implement efficient breeding schemes at early stages of development. Atlantic salmon belongs to the family Salmonidae of fishes and represents a species of great commercial value. Although the species is assumed to be male heterogametic with XY sex determination, the precise genetic basis of sexual development remains unclear. The complexity is likely associated to the relatively recent salmonid specific whole genome duplication that may be responsible for certain genome instability. This instability together with the capacity of the sex-determining gene to move across the genome as reported by previous studies, may explain that sexual development genes are not circumscribed to the same chromosomes in all members of the species. In this study, we have used a 220 K SNP panel developed for Atlantic salmon to identify the chromosomes explaining the highest proportion of the genetic variance for sex as well as candidate regions and genes associated to sexual development in this species. Results: Results from regional heritability analysis showed that the chromosomes explaining the highest proportion of variance in these populations were Ssa02 (heritability = 0.42, SE = 0.12) and Ssa21 (heritability = 0.26, SE = 0.11). After pruning by linkage disequilibrium, genome-wide association analyses revealed 114 SNPs that were significantly associated with sex, being Ssa02 the chromosome containing a greatest number of regions. Close examination of the candidate regions evidenced important genes related to sex in other species of Class Actinopterygii, including SDY, genes from family SOX, RSPO1, ESR1, U2AF2A, LMO7, GNRH-R, DND and FIGLA. Conclusions: The combined results from regional heritability analysis and genome-wide association have provided new advances in the knowledge of the genetic regulation of sex determination in Atlantic salmon, supporting that Ssa02 is the candidate chromosome for sex in this species and suggesting an alternative population lineage in Spanish wild populations according to the results from Ssa21.Ministerio de Economía y Competitividad | Ref. RZ2012–00011-C02–00Ministerio de Ciencia e Innovación | Ref. JCI-2011-1089

The transcriptional and mutational landscapes of lipid metabolism-related genes in colon cancer

Metabolic alterations encountered in tumors are well recognized and considered as a hallmark of cancer. In addition to Warburg Effect, epidemiological and experimental studies support the crucial role of lipid metabolism in colorectal cancer (CRC). The overexpression of four lipid metabolism-related genes (ABCA1, ACSL1, AGPAT1 and SCD genes) has been proposed as prognostic marker of stage II CRC (ColoLipidGene signature). In order to explore in depth the transcriptomic and genomic scenarios of ABCA1, ACSL1, AGPAT1 and SCD genes, we performed a transcriptomic meta-analysis in more than one thousand CRC individuals. Additionally we analyzed their genomic coding sequence in 95 patients, to find variants that could orchestrate CRC prognosis. We found that genetic variant rs3071, located on SCD gene, defines a 9.77% of stage II CRC patients with high risk of death. Moreover, individuals with upregulation of ABCA1 and AGPAT1 expression have an increased risk of CRC recurrence, independently of tumor stage. ABCA1 emerges as one of the main contributors to signature's prognostic effect. Indeed, both high ABCA1 expression and presence of tumoral genetic variants located in ABCA1 coding region, seem to be associated with CRC risk of death. In addition the non-synonymous polymorphism rs2230808, located on ABCA1, is associated with gene expression. Patients carrying at least one copy of minor allele showed higher levels of ABCA1 expression than patients carrying homozygous major allele. This study broaden the prognostic value of ABCA1, ACSL1, AGPAT1 and SCD genes, independently of CRC tumor stage, leading to future precision medicine approaches and "omics"-guided therapiesMinisterio de Economía y Competitividad del Gobierno de España (MINECO, Plan Nacional I+D+i AGL2016-76736-C3), Gobierno regional de la Comunidad de Madrid (P2013/ABI-2728, ALIBIRD-CM) and EU Structural Fund

Sex-specific genetic effects associated with pigmentation, sensitivity to sunlight, and melanoma in a population of Spanish origin

Background Human pigmentation is a polygenic quantitative trait with high heritability. In addition to genetic factors, it has been shown that pigmentation can be modulated by oestrogens and androgens via up- or down-regulation of melanin synthesis. Our aim was to identify possible sex differences in pigmentation phenotype as well as in melanoma association in a melanoma case-control population of Spanish origin. Methods Five hundred and ninety-nine females (316 melanoma cases and 283 controls) and 458 males (234 melanoma cases and 224 controls) were analysed. We genotyped 363 polymorphisms (single nucleotide polymorphisms (SNPs)) from 65 pigmentation gene regions. Results When samples were stratified by sex, we observed more SNPs associated with dark pigmentation and good sun tolerance in females than in males (107 versus 75; P = 2.32 × 10−6), who were instead associated with light pigmentation and poor sun tolerance. Furthermore, six SNPs in TYR, SILV/CDK2, GPR143, and F2RL1 showed strong differences in melanoma risk by sex (P < 0.01). Conclusions We demonstrate that these genetic variants are important for pigmentation as well as for melanoma risk, and also provide suggestive evidence for potential differences in genetic effects by sex.We thank the Madrid College of Lawyers and all patients from the different contributing Hospitals. We would like to thank Tais Moreno, M. Rosario Alonso, and Guillermo Pita for their expert technical assistance with Illumina genotyping, performed at the Spanish National Genotyping Centre (CeGen, Madrid). MI-V is funded by the “Ministry of Health Carlos III” under a Sara Borrell contract (CD15/00153). ML-C is funded by a Prometeo contract (2015/005). SSO is funded by the “ Ministry of Education, Culture and Sport” under a FPU fellowship (FPU13/04976). GR is funded by the “Ministry of Health Carlos III” under a Miquel Servet II contract (CPII14-00013). This work has also been partly funded by a research project from the Spanish Ministry of Economy and Competitiveness (CGL2014-58526-P), whose principal investigator is S

The OTELO survey. A case study of [O III]4959,5007 emitters at <z> = 0.83

The OTELO survey is a very deep, blind exploration of a selected region of the Extended Groth Strip and is designed for finding emission-line sources (ELSs). The survey design, observations, data reduction, astrometry, and photometry, as well as the correlation with ancillary data used to obtain a final catalogue, including photo-z estimates and a preliminary selection of ELS, were described in a previous contribution. Here, we aim to determine the main properties and luminosity function (LF) of the [O III] ELS sample of OTELO as a scientific demonstration of its capabilities, advantages, and complementarity with respect to other surveys. The selection and analysis procedures of ELS candidates obtained using tunable filter (TF) pseudo-spectra are described. We performed simulations in the parameter space of the survey to obtain emission-line detection probabilities. Relevant characteristics of [O III] emitters and the LF([O III]), including the main selection biases and uncertainties, are presented. A total of 184 sources were confirmed as [O III] emitters at a mean redshift z=0.83. The minimum detectable line flux and equivalent width (EW) in this ELS sample are $\sim$5 $\times$ 10$^{-19}$ erg s$^{-1}$ cm$^{2}$ and $\sim$6 \AA, respectively. We are able to constrain the faint-end slope ($\alpha = -1.03\pm0.08$) of the observed LF([O III]) at z=0.83. This LF reaches values that are approximately ten times lower than those from other surveys. The vast majority (84\%) of the morphologically classified [O III] ELSs are disc-like sources, and 87\% of this sample is comprised of galaxies with stellar masses of M$_\star$ $<$ 10$^{10}$ M$_{\odot}$.Comment: v1: 16 pages, 6 figures. Accepted in Astronomy \& Astrophysics. v2: Author added in metadat

Galaxy classification: deep learning on the OTELO and COSMOS databases

Context. The accurate classification of hundreds of thousands of galaxies observed in modern deep surveys is imperative if we want to understand the universe and its evolution. Aims. Here, we report the use of machine learning techniques to classify early- and late-type galaxies in the OTELO and COSMOS databases using optical and infrared photometry and available shape parameters: either the Sersic index or the concentration index. Methods. We used three classification methods for the OTELO database: 1) u-r color separation , 2) linear discriminant analysis using u-r and a shape parameter classification, and 3) a deep neural network using the r magnitude, several colors, and a shape parameter. We analyzed the performance of each method by sample bootstrapping and tested the performance of our neural network architecture using COSMOS data. Results. The accuracy achieved by the deep neural network is greater than that of the other classification methods, and it can also operate with missing data. Our neural network architecture is able to classify both OTELO and COSMOS datasets regardless of small differences in the photometric bands used in each catalog. Conclusions. In this study we show that the use of deep neural networks is a robust method to mine the cataloged dataComment: 20 pages, 10 tables, 14 figures, Astronomy and Astrophysics (in press

An upper limit for the water outgassing rate of the main-belt comet 176P/LINEAR observed with Herschel/HIFI

176P/LINEAR is a member of the new cometary class known as main-belt comets (MBCs). It displayed cometary activity shortly during its 2005 perihelion passage that may be driven by the sublimation of sub-surface ices. We have therefore searched for emission of the H2O 110-101 ground state rotational line at 557 GHz toward 176P/LINEAR with the Heterodyne Instrument for the Far Infrared (HIFI) on board the Herschel Space Observatory on UT 8.78 August 2011, about 40 days after its most recent perihelion passage, when the object was at a heliocentric distance of 2.58 AU. No H2O line emission was detected in our observations, from which we derive sensitive 3-sigma upper limits for the water production rate and column density of < 4e25 molec/s and of < 3e10 cm^{-2}, respectively. From the peak brightness measured during the object's active period in 2005, this upper limit is lower than predicted by the relation between production rates and visual magnitudes observed for a sample of comets by Jorda et al. (2008) at this heliocentric distance. Thus, 176P/LINEAR was likely less active at the time of our observation than during its previous perihelion passage. The retrieved upper limit is lower than most values derived for the H2O production rate from the spectroscopic search for CN emission in MBCs.Comment: 5 pages, 2 figures. Minor changes to match published versio