Elizabeth Langley

Instituto Nacional de Cancerología

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Co-Authors

Sean Maguire

GlaxoSmithKline (United States)

Ruby Banerjee

Wellcome Sanger Institute

Beiyuan Fu

Wellcome Sanger Institute

Nigel P. Carter

Wellcome Sanger Institute

Fengtang Yang

Shandong University of Technology

Steve Searle

St Richard's Hospital

R. E. Hall

Wellcome Sanger Institute

Deborah Wright

Auckland District Health Board

John H. Burton

Australian National University

Sean Humphray

Illumina (United Kingdom)

Cooperative Institutions

Wellcome Sanger Institute

168

Max Planck Institute for Developmental Biology

140

University of Cambridge

Wellcome Trust

European Bioinformatics Institute

University College London

University of Edinburgh

Centre National de la Recherche Scientifique

Harvard University

National Institute of Genomic Medicine

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Abstract C56: Characterization of PinX1 as a coregulator of steroid hormone receptors

Cancer Research (2011)

Yamilet Noriega Miguel Rivas Elizabeth Langley

Abstract Introduction: Deregulated expression of transcriptional coactivators and corepressors has been implicated in tamoxifen (TAM) resistance, especially in ER+ breast cancer patients. The AF-1 transcriptional activation domain in the N-terminus of ER has been implicated in the tissue specific agonistic effects of TAM. Thus, using the yeast two-hybrid system with the N-terminal region of ERα, we located the PINX1 gene which encodes for a telomerase inhibitor. Objective: In this work, we characterized PinX1 as a coregulator of ERα. Methods and Results: Using GST pull-down assays, we confirmed the direct interaction between PinX1 and the N-terminus of ERα, showing no interaction with the C-terminus either in the presence or absence of estradiol (E2). Transcriptional activation assays using luciferase reporter genes show that PinX1 is capable of increasing ERα transcriptional activity in breast cancer cell lines, at low concentrations, but increasing PinX1 exhibits a negative effect on the transcriptional activity of ERα in these cell lines. However, Pinx1 repressed AF-1 transcriptional activity, as well as AF-2 activity in the presence of E2. ChIP assays verified that the interaction between ERα and Pinx1 occurs on E2 regulated promoters after 2h of incubation with E2. Furthermore, PinX1 inhibits E2 induced proliferation of MCF7 cells, while inhibition of PinX1 by siRNA increases E2 induced proliferation. These results suggest a role for PinX1 as a correpresor of ERα. PinX1 also interacts with the androgen and progesterone receptors. However, we demonstrate that PinX1 is a coactivator of these receptors by luciferase assays, as well as increasing DHT induced proliferation of prostate cancer cell lines. Enhanced expression of PinX1 also deregulates the expression of a number of genes that have a role in cell growth and proliferation in breast cancer cell lines. Conclusions: Our data support a dual role for PinX1 as a correpresor of ERα and a coactivator of AR and PR. Additionally, it may be involved in functions regulating cell growth and proliferation in both breast and prostate cancer cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C56.

Hormone response element

10.1158/1538-7445.fbcr11-c56

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The zebrafish reference genome sequence and its relationship to the human genome

Nature (2013)

Kerstin Howe Matthew D. Clark Carlos Torroja James Torrance Camille Berthelot

A high-quality sequence assembly of the zebrafish genome reveals the largest gene set of any vertebrate and provides information on key genomic features, and comparison to the human reference genome shows that approximately 70% of human protein-coding genes have at least one clear zebrafish orthologue. The genome of the zebrafish — a key model organism for the study of development and human disease — has now been sequenced and published as a well-annotated reference genome. Zebrafish turns out to have the largest gene set of any vertebrate so far sequenced, and few pseudogenes. Importantly for disease studies, comparison between human and zebrafish sequences reveals that 70% of human genes have at least one obvious zebrafish orthologue. A second paper reports on an ongoing effort to identify and phenotype disruptive mutations in every zebrafish protein-coding gene. Using the reference genome sequence along with high-throughput sequencing and efficient chemical mutagenesis, the project's initial results — covering 38% of all known protein-coding genes — they describe phenotypic consequences of more than 1,000 alleles. The long-term goal is the creation of a knockout allele in every protein-coding gene in the zebrafish genome. All mutant alleles and data are freely available at go.nature.com/en6mos . Zebrafish have become a popular organism for the study of vertebrate gene function1,2. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease3,4,5. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes6, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

Pseudogene

Model Organism

10.1038/nature12111

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Citations (4,368)

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Journal of Biological Chemistry (1995)

Sunil Ahuja Philip Murphy Małgorzata Wilczyńska Ming Fa Tor Ohlsson

Binding of molten globule-like conformations to lipid bilayers.

Molten globule

10.1016/s0021-9258(17)45858-3

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Exosomal lncRNAs as regulators of breast cancer chemoresistance and metastasis and their potential use as biomarkers

Frontiers in Oncology (2024)

Sugela Susana Blancas-Zugarazo Elizabeth Langley Alfredo Hidalgo‐Miranda

Breast cancer is the most common cancer in women and the leading cause of female deaths by cancer in the world worldwide. Hence, understanding the molecular mechanisms associated with breast cancer development and progression, including drug resistance and breast cancer metastasis, is essential for achieving the best management of breast cancer patients. Cancer-related long noncoding RNAs have been shown to be involved in the regulation of each stage of breast cancer progression. Additionally, exosomes are extracellular microvesicles that are central to intercellular communication and play an important role in tumorigenesis. Exosomes can be released from primary tumor cells into the bloodstream and transmit cellular signals to distant body sites. In this work, we review the findings regarding the cellular mechanisms regulated by exosomal lncRNAs that are essentials to chemoresistance development and metastasis of breast cancer. Likewise, we evaluate the outcomes of the potential clinical use of exosomal lncRNAs as breast cancer biomarkers to achieve personalized management of the patients. This finding highlights the importance of transcriptomic analysis of exosomal lncRNAs to understand the breast cancer tumorigenesis as well as to improve the clinical tests available for this disease.

10.3389/fonc.2024.1419808

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Citations (3)

cellsrat hepatocytes and human hepatoblastoma Regulation by glucagon of the rat histidase gene promoter

Gabriela Alemán Víctor Ortiz‐García de la Foz Elizabeth Langley Armando R. Tovar Nimbe Torres

Hepatoblastoma

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SFRP1 increases TMPRSS2-ERG expression promoting neoplastic features in prostate cancer in vitro and in vivo

Cancer Cell International (2020)

Carlos D. Cruz-Hernández Marian Cruz-Burgos Sergio A. Cortés-Ramírez Alberto Losada-García Ignacio Camacho‐Arroyo

Prostate cancer (PCa) is the second cause of cancer related death in North American men. Androgens play an important role in its progression by regulating the expression of several genes including fusion ones that results from structural chromosome rearrangements. TMPRSS2-ERG is a fusion gene commonly observed in over 50% of PCa tumors, and its expression can be transcriptionally regulated by the androgen receptor (AR) given its androgen responsive elements. TMPRSS2-ERG could be involved in epithelial-mesenchymal transition (EMT) during tumor development. ERG has been reported as a key transcriptional factor in the AR-ERG-WNT network where five SFRP proteins, structurally similar to WNT ligands and considered to be WNT pathway antagonists, can regulate signaling in the extracellular space by binding to WNT proteins or Frizzled receptors. It has been shown that over-expression of SFRP1 protein can regulate the transcriptional activity of AR and inhibits the formation of colonies in LNCaP cells. However, the effect of SFRP1 has been controversial since differential effects have been observed depending on its concentration and tissue location. In this study, we explored the role of exogenous SFRP1 protein in cells expressing the TMPRSS2-ERG fusion.To evaluate the effect of exogenous SFRP1 protein on PCa cells expressing TMPRSS2-ERG, we performed in silico analysis from TCGA cohort, expression assays by RT-qPCR and Western blot, cell viability and cell cycle measurements by cytometry, migration and invasion assays by xCELLigance system and murine xenografts.We demonstrated that SFRP1 protein increased ERG expression by promoting cellular migration in vitro and increasing tumor growth in vivo in PCa cells with the TMPRSS2-ERG fusion.These results suggest the possible role of exogenous SFRP1 protein as a modulator of AR-ERG-WNT signaling network in cells positive to TMPRSS2-ERG. Further, investigation is needed to determine if SFRP1 protein could be a target in against this type of PCa.

TMPRSS2

Erg

10.1186/s12935-020-01333-5

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Citations (8)

Copy number variation, chromosome rearrangement, and their association with recombination during avian evolution

Genome Research (2010)

Martin A. Volker Niclas Backström Benjamin M. Skinner Elizabeth Langley Sydney K. Bunzey

Chromosomal rearrangements and copy number variants (CNVs) play key roles in genome evolution and genetic disease; however, the molecular mechanisms underlying these types of structural genomic variation are not fully understood. The availability of complete genome sequences for two bird species, the chicken and the zebra finch, provides, for the first time, an ideal opportunity to analyze the relationship between structural genomic variation (chromosomal and CNV) and recombination on a genome-wide level. The aims of this study were therefore threefold: (1) to combine bioinformatics, physical mapping to produce comprehensive comparative maps of the genomes of chicken and zebra finch. In so doing, this allowed the identification of evolutionary chromosomal rearrangements distinguishing them. The previously reported interchromosomal conservation of synteny was confirmed, but a larger than expected number of intrachromosomal rearrangements were reported; (2) to hybridize zebra finch genomic DNA to a chicken tiling path microarray and identify CNVs in the zebra finch genome relative to chicken; 32 interspecific CNVs were identified; and (3) to test the hypothesis that there is an association between CNV, chromosomal rearrangements, and recombination by correlating data from (1) and (2) with recombination rate data from a high-resolution genetic linkage map of the zebra finch. We found a highly significant association of both chromosomal rearrangements and CNVs with elevated recombination rates. The results thus provide support for the notion of recombination-based processes playing a major role in avian genome evolution.

Synteny

Chromosomal rearrangement

Comparative genomic hybridization

Non-allelic homologous recombination

10.1101/gr.103663.109

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Citations (147)

Case Report: Novel pathogenic variant in NFIX in two sisters with Malan syndrome due to germline mosaicism

Frontiers in Genetics (2022)

Elizabeth Langley Laura S. Farach Kate Mowrey

Malan syndrome is an autosomal dominant disorder caused by pathogenic variants in NFIX with less than 100 cases reported thus far. NFIX is important for stem cell proliferation, quiescence, and differentiation during development and its protein plays a role in replication, signal transduction, and transcription. As a result of pathogenic variants, symptoms of Malan syndrome include overgrowth, intellectual disability, speech delay, and dysmorphic features. Currently, the recurrence risk for this disorder is indicated at less than 1%, standard for de novo autosomal dominant disorders. Herein, we report an additional set of sisters with the same novel pathogenic variant in NFIX and clinical features consistent with Malan syndrome providing evidence of germline mosaicism. Considering the rarity of this condition in conjunction with three previous reports of germline mosaicism, it is worthwhile to investigate and re-evaluate the proper recurrence risk for this condition. This discovery would be paramount for family planning and genetic counseling practices in families with affected individuals.

Genetic disorder

10.3389/fgene.2022.1044660

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Massively Parallel Sequencing Reveals the Complex Structure of an Irradiated Human Chromosome on a Mouse Background in the Tc1 Model of Down Syndrome

PLoS ONE (2013)

Susan Gribble Frances K. Wiseman Stephen Clayton Elena Prigmore Elizabeth Langley

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.

Massive parallel sequencing

10.1371/journal.pone.0060482

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Citations (102)

Regulation of the rat branched‐chain aminotransferase gene promoter by HNF4

The FASEB Journal (2006)

Tania R Orozco Carolina Flores Gabriela Alemán Elizabeth Langley Nimbe Torres

The first step in the catabolism of branched-chain amino acids (BCAA) is catalyzed by the mitochondrial (m) and cytosolic (c) branched chain aminotransferase (BCAT). BCATm is a constitutive enzyme that is expressed in all tissues, except liver, and is induced only under conditions of rapid cell proliferation in fetal liver, hepatoma, and lactating mammary gland. At the present, it is not known how this gene is regulated. Therefore, the purpose of this work was to isolate and analyze the promoter of BCATm. The transcription start site was located at 82 bp from ATG. The promoter segment of 1100 bp does not contain a consensus TATA-box, but it has several Sp1, C/EBP, Oct1, MEF-2, HNF3, HNF4 and RAR response elements. Deletion of HNF4 cis-acting elements resulted in significant reduction of luciferase activity. On the other hand, cotransfection in HepG2 or RIN-m5f cells with the plasmid pHNF4□, increased the activity of luciferase by about 2-fold. In addition, transfection of HepG2 with pHNF4a, also increased the activity of endogenous BCATm. These results indicate that the expression of BCATm gene is in part regulated by the transcription factor HNF4□

Transcription

Hepatocyte nuclear factors

TATA box

Catabolism

10.1096/fasebj.20.5.a1042

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