Estrogen Receptor-α Suppresses Liver Carcinogenesis and Establishes Sex-Specific Gene Expression

Estrogen protects females from hepatocellular carcinoma (HCC). To determine whether this protection is mediated by classic estrogen receptors, we tested HCC susceptibility in estrogen receptor-deficient mice. In contrast to a previous study, we found that diethylnitrosamine induces hepatocarcinogenesis to a significantly greater extent when females lack Esr1, which encodes Estrogen Receptor-α. Relative to wild-type littermates, Esr1 knockout females developed 9-fold more tumors. Deficiency of Esr2, which encodes Estrogen Receptor-β, did not affect liver carcinogenesis in females. Using microarrays and QPCR to examine estrogen receptor effects on hepatic gene expression patterns, we found that germline Esr1 deficiency resulted in the masculinization of gene expression in the female liver. Six of the most dysregulated genes have previously been implicated in HCC. In contrast, Esr1 deletion specifically in hepatocytes of Esr1 conditional null female mice (in which Cre was expressed from the albumin promoter) resulted in the maintenance of female-specific liver gene expression. Wild-type adult females lacking ovarian estrogen due to ovariectomy, which is known to make females susceptible to HCC, also maintained female-specific expression in the liver of females. These studies indicate that Esr1 mediates liver cancer risk, and its control of sex-specific liver gene expression involves cells other than hepatocytes.

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A genomic analysis and transcriptomic atlas of gene expression inPsoroptes ovisreveals feeding- and stage-specific patterns of allergen expression

10.1101/578120 ◽

2019 ◽

Cited By ~ 1

Author(s):

Stewart TG Burgess ◽

Edward J Marr ◽

Kathryn Bartley ◽

Francesca G Nunn ◽

Rachel E Down ◽

...

Keyword(s):

Gene Expression ◽

Expression Patterns ◽

Draft Genome ◽

Genomic Analysis ◽

Gene Clusters ◽

Specific Gene ◽

Multigene Families ◽

Psoroptes Ovis ◽

Specific Expression ◽

Development Of Resistance

ABSTRACTPsoroptic mange, caused by infestation with the ectoparasitic mite,Psoroptes ovis, is highly contagious, resulting in intense pruritus and represents a major welfare and economic concern for the livestock industry Worldwide. Control relies on injectable endectocides and organophosphate dips, but concerns over residues, environmental contamination, and the development of resistance threaten the sustainability of this approach, highlighting interest in alternative control methods. However, development of vaccines and identification of chemotherapeutic targets is hampered by the lack ofP. ovistranscriptomic and genomic resources. Building on the recent publication of theP. ovisdraft genome, here we present a genomic analysis and transcriptomic atlas of gene expression inP. ovisrevealing feeding- and stage-specific patterns of gene expression, including novel multigene families and allergens. Network-based clustering revealed 14 gene clusters demonstrating either single- or multi-stage specific gene expression patterns, with 3,075 female-specific, 890 male-specific and 112, 217 and 526 transcripts showing larval, protonymph and tritonymph specific-expression, respectively. Detailed analysis ofP. ovisallergens revealed stage-specific patterns of allergen gene expression, many of which were also enriched in “fed” mites and tritonymphs, highlighting an important feeding-related allergenicity in this developmental stage. Pair-wise analysis of differential expression between life-cycle stages identified patterns of sex-biased gene expression and also identified novelP. ovismultigene families including known allergens and novel genes with high levels of stage-specific expression. The genomic and transcriptomic atlas described here represents a unique resource for the acarid-research community, whilst the OrcAE platform makes this freely available, facilitating further community-led curation of the draftP. ovisgenome.

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Epigenetic Remodeling in Innate Immunity and Inflammation

Annual Review of Immunology ◽

10.1146/annurev-immunol-093019-123619 ◽

2021 ◽

Vol 39 (1) ◽

Author(s):

Qian Zhang ◽

Xuetao Cao

Keyword(s):

Gene Expression ◽

Innate Immunity ◽

Regulatory Element ◽

Expression Patterns ◽

Innate Immune ◽

Annual Review ◽

Specific Gene ◽

Publication Date ◽

Specific Expression ◽

Epigenetic Remodeling

The innate immune response is a rapid response to pathogens or danger signals. It is precisely activated not only to efficiently eliminate pathogens but also to avoid excessive inflammation and tissue damage. cis-Regulatory element–associated chromatin architecture shaped by epigenetic factors, which we define as the epiregulome, endows innate immune cells with specialized phenotypes and unique functions by establishing cell-specific gene expression patterns, and it also contributes to resolution of the inflammatory response. In this review, we focus on two aspects: ( a) how niche signals during lineage commitment or following infection and pathogenic stress program epiregulomes by regulating gene expression levels, enzymatic activities, or gene-specific targeting of chromatin modifiers and ( b) how the programed epiregulomes in turn mediate regulation of gene-specific expression, which contributes to controlling the development of innate cells, or the response to infection and inflammation, in a timely manner. We also discuss the effects of innate immunometabolic rewiring on epiregulomes and speculate on several future challenges to be encountered during the exploration of the master regulators of epiregulomes in innate immunity and inflammation. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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The Regulator of Sex-Limitation Gene, Rsl, Enforces Male-Specific Liver Gene Expression by Negative Regulation

Endocrinology ◽

10.1210/en.2002-0190 ◽

2003 ◽

Vol 144 (5) ◽

pp. 1854-1860 ◽

Cited By ~ 27

Author(s):

Kathryn M. Tullis ◽

Christopher J. Krebs ◽

Janet Y. M. Leung ◽

Diane M. Robins

Keyword(s):

Gene Expression ◽

Expression Patterns ◽

Specific Gene ◽

Adult Males ◽

Gh Secretion ◽

Hormonal Induction ◽

Sex Limitation ◽

Liver Gene ◽

Limited Protein ◽

Male Specific

Expression of a broad array of proteins is sexually dimorphic in rodent liver, dependent on sex-specific patterns of GH secretion. Mice carrying rsl (regulator of sex limitation) alleles, discovered as trans-acting loci affecting the mouse sex-limited protein (Slp) gene, reveal an additional axis in male-specific gene regulation. Slp expresses in adult males, but in rsl homozygous mice, Slp is also expressed in females. In this study, we examined congenic rsl strains to determine rsl’s site of action, breadth of targets, and interaction with hormonal induction. We show that rsl affects Slp in liver, but not kidney, and that Rsl acts on a spectrum of male-specific liver genes, including mouse urinary proteins and a cytochrome P450 expressed predominantly by males, Cyp 2d-9, but does not act on the female-prominent P450, Cyp 2a-4. Slp expression in hypophysectomized or Tfm/Y rsl mice reveals that Rsl action is independent of GH or androgen signaling. Further, parabiosis of Rsl and rsl mice does not alter expression patterns, consistent with rsl action being liver intrinsic. Finally, Slp expression initiates earlier in rsl mice, suggesting that Rsl operates before, as well as independently of, hormonal induction. This characterization suggests Rsl functions to repress transcription of a set of genes that have in common their hormonal induction in male liver, and thus accentuates sexual dimorphism of liver gene expression.

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A genomic analysis and transcriptomic atlas of gene expression in Psoroptes ovis reveals feeding- and stage-specific patterns of allergen expression

BMC Genomics ◽

10.1186/s12864-019-6082-6 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 5

Author(s):

Stewart T. G. Burgess ◽

Edward J. Marr ◽

Kathryn Bartley ◽

Francesca G. Nunn ◽

Rachel E. Down ◽

...

Keyword(s):

Gene Expression ◽

Expression Patterns ◽

Draft Genome ◽

Genomic Analysis ◽

Gene Clusters ◽

Specific Gene ◽

Multigene Families ◽

Psoroptes Ovis ◽

Specific Expression ◽

Development Of Resistance

Abstract Background Psoroptic mange, caused by infestation with the ectoparasitic mite, Psoroptes ovis, is highly contagious, resulting in intense pruritus and represents a major welfare and economic concern for the livestock industry Worldwide. Control relies on injectable endectocides and organophosphate dips, but concerns over residues, environmental contamination, and the development of resistance threaten the sustainability of this approach, highlighting interest in alternative control methods. However, development of vaccines and identification of chemotherapeutic targets is hampered by the lack of P. ovis transcriptomic and genomic resources. Results Building on the recent publication of the P. ovis draft genome, here we present a genomic analysis and transcriptomic atlas of gene expression in P. ovis revealing feeding- and stage-specific patterns of gene expression, including novel multigene families and allergens. Network-based clustering revealed 14 gene clusters demonstrating either single- or multi-stage specific gene expression patterns, with 3075 female-specific, 890 male-specific and 112, 217 and 526 transcripts showing larval, protonymph and tritonymph specific-expression, respectively. Detailed analysis of P. ovis allergens revealed stage-specific patterns of allergen gene expression, many of which were also enriched in “fed” mites and tritonymphs, highlighting an important feeding-related allergenicity in this developmental stage. Pair-wise analysis of differential expression between life-cycle stages identified patterns of sex-biased gene expression and also identified novel P. ovis multigene families including known allergens and novel genes with high levels of stage-specific expression. Conclusions The genomic and transcriptomic atlas described here represents a unique resource for the acarid-research community, whilst the OrcAE platform makes this freely available, facilitating further community-led curation of the draft P. ovis genome.

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Finding cell-specific expression patterns in the early Ciona embryo with single-cell RNA-seq

10.1101/197699 ◽

2017 ◽

Author(s):

Garth R. Ilsley ◽

Ritsuko Suyama ◽

Takeshi Noda ◽

Nori Satoh ◽

Nicholas M. Luscombe

Keyword(s):

Gene Expression ◽

Single Cell ◽

Expression Patterns ◽

Cell Types ◽

Specific Gene ◽

Rna Seq ◽

Cell Stage ◽

Specific Expression ◽

Temporal Gene Expression

AbstractSingle-cell RNA-seq has been established as a reliable and accessible technique enabling new types of analyses, such as identifying cell types and studying spatial and temporal gene expression variation and change at single-cell resolution. Recently, single-cell RNA-seq has been applied to developing embryos, which offers great potential for finding and characterising genes controlling the course of development along with their expression patterns. In this study, we applied single-cell RNA-seq to the 16-cell stage of the Ciona embryo, a marine chordate and performed a computational search for cell-specific gene expression patterns. We recovered many known expression patterns from our single-cell RNA-seq data and despite extensive previous screens, we succeeded in finding new cell-specific patterns, which we validated by in situ and single-cell qPCR.

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Single cell RNA-seq study of wild type and Hox9,10,11 mutant developing uterus

10.1101/395574 ◽

2018 ◽

Cited By ~ 1

Author(s):

Michael L. Mucenski ◽

Robert Mahoney ◽

Mike Adam ◽

Andrew S. Potter ◽

S. Steven Potter

Keyword(s):

Gene Expression ◽

Single Cell ◽

Hox Genes ◽

Expression Patterns ◽

Wild Type Mouse ◽

Cell Types ◽

Specific Gene ◽

Rna Seq ◽

Wild Type ◽

Mouse Uterus

AbstractThe uterus is a remarkable organ that must guard against infections while maintaining the ability to support growth of a fetus without rejection. The Hoxa10 and Hoxa11 genes have previously been shown to play essential roles in uterus development and function. In this report we show that the Hoxc9,10,11 genes play a redundant role in the formation of uterine glands. In addition, we use single cell RNA-seq to create a high resolution gene expression atlas of the developing wild type mouse uterus. Cell types and subtypes are defined, for example dividing endothelial cells into arterial, venous, capillary, and lymphatic, while epithelial cells separate into luminal and glandular subtypes. Further, a surprising heterogeneity of stromal and myocyte cell types are identified. Transcription factor codes and ligand/receptor interactions are characterized. We also used single cell RNA-seq to globally define the altered gene expression patterns in all developing uterus cell types for two Hox mutants, with 8 or 9 mutant Hox genes. The mutants show a striking disruption of Wnt signaling as well as the Cxcl12/Cxcr4 ligand/receptor axis.Summary statementA single cell RNA-seq study of the developing mouse uterus defines cellular heterogeneities, lineage specific gene expression programs and perturbed pathways in Hox9,10,11 mutants.

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Stable Inhibition of Specific Estrogen Receptor α (ERα) Phosphorylation Confers Increased Growth, Migration/Invasion, and Disruption of Estradiol Signaling in MCF-7 Breast Cancer Cells

Endocrinology ◽

10.1210/en.2011-2001 ◽

2012 ◽

Vol 153 (9) ◽

pp. 4144-4159 ◽

Cited By ~ 16

Author(s):

B. P. Huderson ◽

T. T. Duplessis ◽

C. C. Williams ◽

H. C. Seger ◽

C. G. Marsden ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Estrogen Receptor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Target Genes ◽

Expression Patterns ◽

Estrogen Receptor Α ◽

Regulated Gene Expression ◽

Mcf 7

Elevated phosphorylation of estrogen receptor α (ERα) at serines 118 (S118) and 167 (S167) is associated with favorable outcome for tamoxifen adjuvant therapy and may serve as surrogate markers for a functional ERα signaling pathway in breast cancer. It is possible that loss of phosphorylation at S118 and/or S167 could disrupt ERα signaling, resulting in aggressive ERα-independent breast cancer cells. To this end, MCF-7 breast cancer cells were stably transfected with an ERα-specific short hairpin RNA that reduced endogenous ERα. The resulting cell line was stably transfected with wild-type ERα (ER-AB cells), or ERα containing serine to alanine mutation at S118 or S167 (S118A cells and S167A cells, respectively). These stable cell lines expressed approximately equivalent ERα compared with parental MCF-7 cells and were evaluated for growth, morphology, migration/invasion, and ERα-regulated gene expression. S118A cells and S167A cells exhibited increased growth and migration/invasion in vitro. Forward- and side-scatter flow cytometry revealed that S167A cells were smaller in size, and both S118A and S167A cells exhibited less cellular complexity. S118A and S167A cells expressed pancytokeratin and membrane localization of β-catenin and did not express vimentin, indicating retention of epithelial lineage markers. Expression of ERα-target genes and other genes regulated by ERα signaling or involved in breast cancer were markedly altered in both S118A and S167A cells. In summary, attenuated phosphorylation of ERα at S118 and S167 significantly affected cellular physiology and behavior in MCF-7 breast cancer cells, resulting in increased growth, migration/invasion, compromised expression of ERα target genes, and markedly altered gene expression patterns.

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Role of STAT5a in regulation of sex-specific gene expression in female but not male mouse liver revealed by microarray analysis

Physiological Genomics ◽

10.1152/physiolgenomics.00055.2007 ◽

2007 ◽

Vol 31 (1) ◽

pp. 63-74 ◽

Cited By ~ 41

Author(s):

Karl H. Clodfelter ◽

Gregory D. Miles ◽

Valerie Wauthier ◽

Minita G. Holloway ◽

Xiaohua Zhang ◽

...

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Intracellular Signaling ◽

Specific Gene ◽

Sexually Dimorphic ◽

Wild Type ◽

Specific Gene Expression ◽

Sex Specificity ◽

Liver Gene ◽

Plasma Gh

Sexual dimorphism in mammalian liver impacts genes affecting hepatic physiology, including inflammatory responses, diseased states, and the metabolism of steroids and foreign compounds. Liver sex specificity is dictated by sex differences in pituitary growth hormone (GH) secretion, with the transcription factor signal transducer and activator of transcription (STAT)5b required for intracellular signaling initiated by the pulsatile male plasma GH profile. STAT5a, a minor liver STAT5 form >90% identical to STAT5b, also responds to sexually dimorphic plasma GH stimulation but is unable to compensate for the loss of STAT5b and the associated loss of sex-specific liver gene expression. A large-scale gene expression study was conducted using 23,574-feature oligonucleotide microarrays and livers of male and female mice, both wild-type and Stat5a-inactivated mice, to elucidate any dependence of liver gene expression on STAT5a. Significant sex differences in expression were found for 2,482 mouse genes, 1,045 showing higher expression in males and 1,437 showing higher expression in females. In contrast to the widespread effects of the loss of STAT5b, STAT5a deficiency had a limited but well-defined impact on liver sex specificity, with 219 of 1,437 female-predominant genes (15%) specifically decreased in expression in STAT5a-deficient female liver. Analysis of liver RNAs from wild-type mice representing three mixed or outbred strains identified 1,028 sexually dimorphic genes across the strains, including 393 female-predominant genes, of which 89 (23%) required STAT5a for normal expression in female liver. These findings highlight the importance of STAT5a for regulation of sex-specific gene expression specifically in female liver, in striking contrast to STAT5b, whose major effects are restricted to male liver.

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124 THE MAJOR GENE EXPRESSION PATTERNS IN ENDOMETRIAL TISSUE OF PIGS DURING EARLY GESTATION

Reproduction Fertility and Development ◽

10.1071/rdv17n2ab124 ◽

2005 ◽

Vol 17 (2) ◽

pp. 212

Author(s):

B.-K. Kim ◽

H.J. Chung ◽

Y.G. Ko ◽

Y.M. Kim ◽

H.-H. Seong ◽

...

Keyword(s):

Gene Expression ◽

Estrogen Receptor ◽

Protein Expression ◽

Expression Patterns ◽

Estrogen Receptor Α ◽

Endometrial Tissue ◽

Estrogen Receptor Β ◽

Uterine Receptivity ◽

Early Gestation ◽

Tgf Β1

Although the expression of important genes in the embryo at pre-implantation stage, which encompasses the period from fertilization to implantation, have been reported for mice and cows, little information relevant to this subject is known in pigs. The objective of this study was to investigate the changes of importantly expressed genes and proteins in endometrial tissue of pigs from fertilization to implantation. Six genes, including estrogen receptor-α, estrogen receptor-β, LIF, LR (LIF receptor), TGFβ1, and TGFβ2, that may play important roles in regulating uterine receptivity and successful implantation and that show different expression patterns by the stages of pregnancy were selected. As a step toward understanding the role of gene and protein expression changes in endometrial tissue of pigs during the preimplantation stage (Day 2, Day 6, Day 8, Day 12, and Day 17, n = 3/group) and the post-implantation stage (Day 21 and Day 33, n = 3/group) and Day 0 (estrous), real-time PCR methods for quantitative analysis of genes and immunohistochemistry methods to localize protein expression were utilized. Data from quantitative real-time PCR were analyzed by ANOVA. The results of this experiment indicated that estrogen receptor-β mRNA level was sharply increased to Day 12 of pregnancy, while estrogen receptor-α mRNA did not change drastically during early pregnancy stage. In contrast, levels of LIF and LR mRNA were increased from Day 2 to Day 33. Although TGFβ1 mRNA reached peak on Day 17 and TGFβ2 mRNA showed the highest level on Day 17, TGFβ2 did not appear to change drastically. For the protein expression patterns, estrogen receptor-α and estrogen receptor-β proteins were expressed in both luminal epithelium and glandular epithelium, but they were only partially expressed in some tissues of stroma cells. LIF protein was expressed in all cell types, while TGF β1 protein was high expressed in glandular epithelium. Also, ERs, LIF, and TGF β1 mRNA and protein expression showed stage- and cell-specific expression patterns. We also investigated the gene expression of TGF β1 mRNA and TGF β2 mRNA in early conceptus (Day 12 and Day 17). TGF β1 mRNA expression was low in Day 12 embryos, and increased progressively to Day 17. This indicated that both the maternal uterus and the conceptus represent the same gene expression pattern. These results suggest that estrogen receptor-β could be an important factor in estrogen action in endometrial tissue during early gestation in pigs, and TGF βs function in both autocrine and paracrine interactions. Progressive increase in TGF β1 mRNA expression in conceptus and uterine tissues suggest important roles of TGF β1 in conceptus development and establishment of the uterine receptivity during the peri-implantation period.

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The combined detection of Amphiregulin, Cyclin A1 and DDX20/Gemin3 expression predicts aggressive forms of oral squamous cell carcinoma

British Journal of Cancer ◽

10.1038/s41416-021-01491-x ◽

2021 ◽

Author(s):

Ekaterina Bourova-Flin ◽

Samira Derakhshan ◽

Afsaneh Goudarzi ◽

Tao Wang ◽

Anne-Laure Vitte ◽

...

Keyword(s):

Gene Expression ◽

Squamous Cell ◽

Large Scale ◽

Biomarker Discovery ◽

Gene Expression Signature ◽

Predictive Biomarkers ◽

Specific Gene ◽

Specific Expression ◽

Intrinsic Nature ◽

Independent Cohort

Abstract Background Large-scale genetic and epigenetic deregulations enable cancer cells to ectopically activate tissue-specific expression programmes. A specifically designed strategy was applied to oral squamous cell carcinomas (OSCC) in order to detect ectopic gene activations and develop a prognostic stratification test. Methods A dedicated original prognosis biomarker discovery approach was implemented using genome-wide transcriptomic data of OSCC, including training and validation cohorts. Abnormal expressions of silent genes were systematically detected, correlated with survival probabilities and evaluated as predictive biomarkers. The resulting stratification test was confirmed in an independent cohort using immunohistochemistry. Results A specific gene expression signature, including a combination of three genes, AREG, CCNA1 and DDX20, was found associated with high-risk OSCC in univariate and multivariate analyses. It was translated into an immunohistochemistry-based test, which successfully stratified patients of our own independent cohort. Discussion The exploration of the whole gene expression profile characterising aggressive OSCC tumours highlights their enhanced proliferative and poorly differentiated intrinsic nature. Experimental targeting of CCNA1 in OSCC cells is associated with a shift of transcriptomic signature towards the less aggressive form of OSCC, suggesting that CCNA1 could be a good target for therapeutic approaches.

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