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Papers by Eric Antoniou

Journal of Clinical Endocrinology &amp Metabolism

Estrogen-related receptor beta (ERRbeta) was one of the first two orphan nuclear receptors report... more Estrogen-related receptor beta (ERRbeta) was one of the first two orphan nuclear receptors reported and is believed to play important roles in estrogen-regulated pathways. Embryo lethality of ERRbeta-null mice indicated that ERRbeta is essential for embryo development. Two novel splicing isoforms of human (h) ERRbeta, hERRbeta2-Delta10 and short-form hERRbeta, were identified during the cloning of previously reported hERRbeta-hERRbeta2. We aim to investigate the functional differences of these three human ERRbeta-splicing isoforms. A genomic sequence comparison within and flanking the ERRbeta genes of eight species demonstrated that short-form hERRbeta lacks an F domain and is the matched homolog of mouse and rat ERRbeta proteins in humans. However, hERRbeta2-Delta10 and the previously reported hERRbeta2 isoforms are primate specific. RT-PCR analysis showed that short-form hERRbeta has a wide distribution in the 24 of 27 human tissues and cell lines tested, whereas hERRbeta2 and hER...

Journal of Animal Science

Fescue toxicosis affects wild and domestic animals grazing fescue pasture infected with the endop... more Fescue toxicosis affects wild and domestic animals grazing fescue pasture infected with the endophytic fungus Neotyphodium coenophialum. Signs of fescue toxicosis include increased core body temperature and respiration rate and decreased milk yield and reproductive performance. Laboratory mice also exhibit symptoms of fescue toxicosis, as indicated by reduced growth rate and reproductive performance. Mice were used to study the effects of fescue toxicosis on hepatic gene expression. Twenty-seven mice were randomly allocated to a diet containing either 50% endophyte-infected (E+; 6 ppm ergovaline) or endophyte-free (E-) fescue seed for 2 wk under thermoneutral conditions. Liver genes differentially expressed due to fescue toxicosis were identified using DNA microarray. A 2-stage ANOVA of microarray data identified 36 differentially expressed genes between mice fed E+ and E- diets. Another analysis method, significance analysis of microarray, identified 9 genes as differentially expre...

Journal of Animal Science

Fescue toxicosis is caused by consumption of toxins produced by an endophytic fungus, Neotyphodiu... more Fescue toxicosis is caused by consumption of toxins produced by an endophytic fungus, Neotyphodium coenophialum, in tall fescue [Lolium arundinaceum (Schreb.) Darbysh]. Microarray analysis was used to identify shifts in genetic expression associated with the affected physiological processes to identify potential targets for future pharmacological/toxicological intervention. Male rats (n = 24) were implanted with temperature transmitters, which measure core temperature every 5 min. After an 8-d recovery, the rats were fed an endophyte-free diet for 5 d. During the following 5-d treatment period, rats were fed either an endophyte-free or an endophyte-infected (91.5 microg of ergovaline.kg of BW(-1).d(-1)) diet. At the end of treatment, rats were euthanized and a sample of the liver was obtained. Feed conversion efficiency was calculated for both treatment groups. Serum prolactin concentrations were measured using ELISA. Liver tissue RNA was reverse transcribed and hybridized to an oli...

PLoS ONE, 2014

Background: Colorectal cancer (CRC) has the third highest mortality rates among the US population... more Background: Colorectal cancer (CRC) has the third highest mortality rates among the US population. According to the most recent concept of carcinogenesis, human tumors are organized hierarchically, and the top of it is occupied by malignant stem cells (cancer stem cells, CSCs, or cancer-initiating cells, CICs), which possess unlimited self-renewal and tumor-initiating capacities and high resistance to conventional therapies. To reflect the complexity and diversity of human tumors and to provide clinically and physiologically relevant cancer models, large banks of characterized patient-derived low-passage cell lines, and especially CIC-enriched cell lines, are urgently needed.

Methods in molecular biology (Clifton, N.J.), 2012

Second-generation sequencers such as the Illumina GAIIx make possible the study of all transcribe... more Second-generation sequencers such as the Illumina GAIIx make possible the study of all transcribed loci in a genome across an almost endless dynamic range. Although typical protocols call for starting from at least 1 μg of total RNA, this is not possible when studying small tissues or rare cell types. This chapter explains how to prepare Illumina sequencing libraries from mouse oocytes. The protocol is also suitable for mural and cumulus cells, flow sorted or laser captured cells.

The Journal of clinical endocrinology and metabolism, 2006

Bioinformatics (Oxford, England), Jan 13, 2015

Currently available bisulfite sequencing tools frequently suffer from low mapping rates and low m... more Currently available bisulfite sequencing tools frequently suffer from low mapping rates and low methylation calls, especially for data generated from the Illumina sequencer, NextSeq. Here we introduce a sequential trimming-and-retrieving alignment approach for investigating DNA methylation patterns, which significantly improves the number of mapped reads and covered CpG sites. The method is implemented in an automated analysis toolkit for processing bisulfite sequencing reads. Availability: http://mysbfiles.stonybrook.edu/~xuefenwang/software.html https://github.com/xfwang/BStools CONTACT: xuefeng.wang@stonybrook.edu SUPPLEMENTARY INFORMATION: Supplementary materials are available at Bioinformatics online.

Toxicological Sciences, 2006

Fescue toxicosis affects wild and domestic animals consuming ergot alkaloids contained in tall fe... more Fescue toxicosis affects wild and domestic animals consuming ergot alkaloids contained in tall fescue forage infected with the endophytic fungus, Neotyphodium coenophialum. When animals are consuming infected fescue (E+) forage during periods of elevated ambient temperatures (summer), a range of phenotypic disorders collectively called summer slump is observed. It is characterized by hyperthermia, with an accompanying decrease in feed intake, growth, milk yield, and reproductive fitness. Laboratory mice also exhibit symptoms of fescue toxicosis at thermoneutral (TN) temperature, as indicated by reduced growth rate and reproductive fitness. Our goal was to characterize the differences in gene expression in liver of mice exposed to summer-type heat stress (HS) and E+ when compared to mice fed E+ at TN temperature. Mice were fed E+ diet under HS (34 ± 1°C; n = 13; E+HS) or TN conditions (24 ± 1°C; n = 14; E+TN) for a period of 2 weeks between 47 and 60 days of age. Genes differentially expressed between E+HS versus E+TN were identified using DNA microarrays. Forty-one genes were differentially expressed between treatment groups. Expressions of eight genes were measured using quantitative real-time PCR. Genes coding for phase I detoxification enzymes were upregulated in E+HS mouse liver. This detoxification pathway is known to produce reactive oxidative species. We observed an upregulation of genes involved in the protection against reactive oxidative species. Key genes involved in de novo lipogenesis and lipid transport were also upregulated. Finally, genes involved in DNA damage control and unfolded protein responses were downregulated.

Theriogenology, 2009

Fertility losses in male mice occur approximately 18-28 d after heat stress. The objective of thi... more Fertility losses in male mice occur approximately 18-28 d after heat stress. The objective of this study was to identify gene expression differences in males highly versus lowly fertile after heat stress. Mature male mice were exposed to heat stress (35 AE 1 8C; n = 50) or thermoneutral (21 AE 1 8C; n = 10) conditions for 24 h (Day 0) and hemicastrated (Day 1) to collect tissue for gene expression analyses. Males were subjected to a mating test from Days 18 to 26 when variation in fertility was anticipated. A fertility index was used to rank heat-stressed males and identify those males resistant and susceptible to heat stress, respectively. Microarray analyses were conducted on testis tissues from control (n = 5), heat stress resistant (n = 5), and heat stress susceptible (n = 5) males, and 225 genes were observed to be differentially expressed (P < 0.05), including genes involved in chaperone (Canx, Hspcb1, and Tcp1) and catalytic (Fkpb6, Psma7, and Idh1) activity. Expression patterns of these genes were confirmed using realtime RT-PCR. Male progeny from selected sires were similarly divergent in fertility after heat stress. Testicular expression levels of Canx, Hspcb, and Tcp1 genes were determined in these progeny. Hspcb expression was moderately heritable (0.31 AE 0.25); however, expression patterns of Canx and Tcp1 were not heritable. #

Reproduction, 2006

The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and struct... more The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (nZ11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; nZ6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; nZ5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P!0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function.

Reproduction, 2007

Interferon-t (IFNT) is released by preimplantation conceptuses of ruminant species and prepares t... more Interferon-t (IFNT) is released by preimplantation conceptuses of ruminant species and prepares the mother for pregnancy. Although one important function is to protect the corpus luteum from the luteolytic activity of prostaglandin-F 2a, IFNT most likely regulates a range of other physiological processes in endometrium. Here, an immortalized cell line from ovine uterine luminal epithelial cells was treated with IFNT for either 8 or 24 h. RNA was subjected to cDNA microarray analysis, with RNA from untreated cells as the reference standard. Of 15 634 genes, 1274 (8%) were IFNT responsive at P!0.01 and 585 at P!0.001 to at least one treatment. Of the latter, 356 were up-regulated and 229 down-regulated. Increasing IFNT concentrations from 10 ng/ml to 10 mg/ml had minor effects, and most genes up-or down-regulated at 8 h were regulated similarly at 24 h. Although IFNT influences many genes implicated in antiviral activity and apoptosis, its action also likely regulates prostaglandin metabolism, growth factors and their receptors, apoptosis and the nuclear factor (NF)-kB cascade, extracellular matrix accretion, angiogenesis, blood coagulation, and inflammation. In particular, it increased mRNA concentrations of genes related to the vascular endothelial growth factor R2 pathway of angiogenesis and down-regulated ones associated with hypoxia. Two genes implicated in the antiluteolytic actions of IFNT (encoding cyclooxygenase-2 and the oxytocin receptor respectively) were downregulated in response to all treatments. IFNT targets a complex range of physiological processes during the establishment of pregnancy.

Poultry Science, 2009

The objective of this study was to determine the effects of dietary aflatoxin B 1 (AFB 1 ) on hep... more The objective of this study was to determine the effects of dietary aflatoxin B 1 (AFB 1 ) on hepatic gene expression in male broiler chicks. Seventy-five 1-d-old male broiler chicks were assigned to 3 dietary treatments (5 replicates of 5 chicks each) from hatch to d 21. The diets contained 0, 1 and 2 mg of AFB 1 /kg of feed. Aflatoxin B 1 reduced (P < 0.05) feed intake, BW gain, serum total proteins, and serum Ca and P, but increased (P < 0.01) liver weights in a dose-dependent manner. Microarray analysis was used to identify shifts in genetic expression associated with the affected physiological processes in chicks fed 0 and 2 mg of AFB 1 / kg of feed to identify potential targets for pharmacological/toxicological intervention. A loop design was used for microarray experiments with 3 technical and 4 biological replicates per treatment group. Ribonucleic acid was extracted from liver tissue, and its quality was determined using gel electrophoresis and spectrophotometry. High-quality RNA was purified from DNA contamination, reverse transcribed, and hybridized to an oligonucleotide microarray chip. Microarray data were analyzed using a 2-step ANOVA model and validated by quantitative real-time PCR of selected genes. Genes with false discovery rates less than 13% and fold change greater than 1.4 were considered differentially expressed. Compared with controls (0 mg of AFB 1 /kg), various genes associated with energy production and fatty acid metabolism (carnitine palmitoyl transferase), growth and development (insulin-like growth factor 1), antioxidant protection (glutathione S transferase), detoxification (epoxide hydrolase), coagulation (coagulation factors IX and X), and immune protection (interleukins) were downregulated, whereas genes associated with cell proliferation (ornithine decarboxylase) were upregulated in birds fed 2 mg of AFB 1 /kg. This study demonstrates that AFB 1 exposure at a concentration of 2 mg/kg results in physiological responses associated with altered gene expression in chick livers.

Poultry Science, 2009

The objective of the present study was to evaluate the efficacy of curcumin, an antioxidant found... more The objective of the present study was to evaluate the efficacy of curcumin, an antioxidant found in turmeric (Curcuma longa) powder (TMP), to ameliorate changes in gene expression in the livers of broiler chicks fed aflatoxin B 1 (AFB 1 ). Four pen replicates of 5 chicks each were assigned to each of 4 dietary treatments, which included the following: A) basal diet containing no AFB 1 or TMP (control), B) basal diet supplemented with TMP (0.5%) that supplied 74 mg/ kg of curcumin, C) basal diet supplemented with 1.0 mg of AFB 1 /kg of diet, and D) basal diet supplemented with TMP that supplied 74 mg/kg of curcumin and 1.0 mg of AFB 1 /kg of diet. Aflatoxin reduced (P < 0.05) feed intake and BW gain and increased (P < 0.05) relative liver weight. Addition of TMP to the AFB 1 diet ameliorated (P < 0.05) the negative effects of AFB 1 on growth performance and liver weight. At the end of the 3-wk treatment period, livers were collected (6 per treatment) to evaluate changes in the expression of genes involved in antioxidant function [catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST)], biotransformation [epoxide hydrolase (EH), cytochrome P450 1A1 and 2H1 (CYP1A1 and CYP2H1)], and the immune system [interleukins 6 and 2 (IL-6 and IL-2)]. Changes in gene expression were determined using the quantitative real-time PCR technique. There was no statistical difference in gene expression among the 4 treatment groups for CAT and IL-2 genes. Decreased expression of SOD, GST, and EH genes due to AFB 1 was alleviated by inclusion of TMP in the diet. Increased expression of IL-6, CYP1A1 and CYP2H1 genes due to AFB 1 was also alleviated by TMP. The current study demonstrates partial protective effects of TMP on changes in expression of antioxidant, biotransformation, and immune system genes in livers of chicks fed AFB 1 . Practical application of the research is supplementation of TMP in diets to prevent or reduce the effects of aflatoxin in chicks fed aflatoxin-contaminated diets.

Oncogene, 2014

The incidence of Barrett's esophagus (BE)-associated esophageal adenocarcinoma (EAC) is increasin... more The incidence of Barrett's esophagus (BE)-associated esophageal adenocarcinoma (EAC) is increasing. Next-generation sequencing (NGS) provides an unprecedented opportunity to uncover genomic alterations during BE pathogenesis and progression to EAC, but treatment-naive surgical specimens are scarce. The objective of this study was to establish the feasibility of using widely available endoscopic mucosal biopsies for successful NGS, using samples obtained from a BE 'progressor'. Paired-end whole-genome NGS was performed on the Illumina platform using libraries generated from mucosal biopsies of normal squamous epithelium (NSE), BE and EAC obtained from a patient who progressed to adenocarcinoma during endoscopic surveillance. Selective validation studies, including Sanger sequencing, immunohistochemistry and functional assays, were performed to confirm the NGS findings. NGS identified somatic nonsense mutations of AT-rich interactive domain 1A (SWI like) (ARID1A) and PPIE and an additional 37 missense mutations in BE and/or EAC, which were confirmed by Sanger sequencing. ARID1A mutations were detected in 15% (3/20) highgrade dysplasia (HGD)/EAC patients. Immunohistochemistry performed on an independent archival cohort demonstrated ARID1A protein loss in 0% (0/76), 4.9% (2/40), 14.3% (4/28), 16.0% (8/50) and 12.2% (12/98) of NSE, BE, low-grade dysplasia, HGD and EAC tissues, respectively, and was inversely associated with nuclear p53 accumulation (P ¼ 0.028). Enhanced cell growth, proliferation and invasion were observed on ARID1A knockdown in EAC cells. In addition, genes downstream of ARID1A that potentially contribute to the ARID1A knockdown phenotype were identified. Our studies establish the feasibility of using mucosal biopsies for NGS, which should enable the comparative analysis of larger 'progressor' versus 'non-progressor' cohorts. Further, we identify ARID1A as a novel tumor-suppressor gene in BE pathogenesis, reiterating the importance of aberrant chromatin in the metaplasiadysplasia sequence.

Neuromuscular Disorders, 1997

The gene for spinocerebellar ataxia 7 (SCA7) has recently been mapped to chromosome 3p12-p13. We ... more The gene for spinocerebellar ataxia 7 (SCA7) has recently been mapped to chromosome 3p12-p13. We have identified by positional cloning a novel gene of unknown function containing a CAG repeat that is expanded in SCA7 patients. On normal alleles, CAG repeat size ...

Nature Genetics, 1997

The gene for spinocerebellar ataxia 7 (SCA7) has been mapped to chromosome 3p12-13. By positional... more The gene for spinocerebellar ataxia 7 (SCA7) has been mapped to chromosome 3p12-13. By positional cloning, we have identified a new gene of unknown function containing a CAG repeat that is expanded in SCA7 patients. On mutated alleles, CAG repeat size is highly variable, ranging from 38 to 130 repeats, whereas on normal alleles it ranges from 7 to 17 repeats. Gonadal instability in SCA7 is greater than that observed in any of the seven known neuro-degenerative diseases caused by translated CAG repeat expansions, and is markedly associated with paternal transmissions. SCA7 is the first such disorder in which the degenerative process also affects the retina.

Journal of Clinical Endocrinology &amp Metabolism

Journal of Animal Science

PLoS ONE, 2014

Methods in molecular biology (Clifton, N.J.), 2012

The Journal of clinical endocrinology and metabolism, 2006

Bioinformatics (Oxford, England), Jan 13, 2015

Toxicological Sciences, 2006

Theriogenology, 2009

Reproduction, 2006

Reproduction, 2007

Poultry Science, 2009

Oncogene, 2014

Neuromuscular Disorders, 1997

Nature Genetics, 1997