scholarly journals Differential brain ADRA2A and ADRA2C gene expression and epigenetic regulation in schizophrenia. Effect of antipsychotic drug treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Iria Brocos-Mosquera ◽  
Patricia Miranda-Azpiazu ◽  
Carolina Muguruza ◽  
Virginia Corzo-Monje ◽  
Benito Morentin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Posttranslational Modifications ◽  
Transcriptional Activation ◽  
Epigenetic Modification ◽  
Gene Promoter ◽  
Antipsychotic Treatment ◽  
Promoter Regions ◽  
Clozapine Treatment ◽  
Dorsolateral Prefrontal

AbstractPostsynaptic α2A-adrenoceptor density is enhanced in the dorsolateral prefrontal cortex (DLPFC) of antipsychotic-treated schizophrenia subjects. This alteration might be due to transcriptional activation, and could be regulated by epigenetic mechanisms such as histone posttranslational modifications (PTMs). The aim of this study was to evaluate ADRA2A and ADRA2C gene expression (codifying for α2-adrenoceptor subtypes), and permissive and repressive histone PTMs at gene promoter regions in the DLPFC of subjects with schizophrenia and matched controls (n = 24 pairs). We studied the effect of antipsychotic (AP) treatment in AP-free (n = 12) and AP-treated (n = 12) subgroups of schizophrenia subjects and in rats acutely and chronically treated with typical and atypical antipsychotics. ADRA2A mRNA expression was selectively upregulated in AP-treated schizophrenia subjects (+93%) whereas ADRA2C mRNA expression was upregulated in all schizophrenia subjects (+53%) regardless of antipsychotic treatment. Acute and chronic clozapine treatment in rats did not alter brain cortex Adra2a mRNA expression but increased Adra2c mRNA expression. Both ADRA2A and ADRA2C promoter regions showed epigenetic modification by histone methylation and acetylation in human DLPFC. The upregulation of ADRA2A expression in AP-treated schizophrenia subjects might be related to observed bivalent chromatin at ADRA2A promoter region in schizophrenia (depicted by increased permissive H3K4me3 and repressive H3K27me3) and could be triggered by the enhanced H4K16ac at ADRA2A promoter. In conclusion, epigenetic predisposition differentially modulated ADRA2A and ADRA2C mRNA expression in DLPFC of schizophrenia subjects.

Mechanisms of mammalian zinc-regulated gene expression

2008 ◽  
Vol 36 (6) ◽  
pp. 1262-1266 ◽  
Author(s):  
Kelly A. Jackson ◽  
Ruth A. Valentine ◽  
Lisa J. Coneyworth ◽  
John C. Mathers ◽  
Dianne Ford
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Repression ◽  
Mammalian Cells ◽  
Gene Promoter ◽  
Mrna Levels ◽  
Promoter Regions ◽  
Mrna Stabilization ◽  
Transcriptional Regulatory ◽  
Regulated Gene Expression

Mechanisms through which gene expression is regulated by zinc are central to cellular zinc homoeostasis. In this context, evidence for the involvement of zinc dyshomoeostasis in the aetiology of diseases, including Type 2 diabetes, Alzheimer's disease and cancer, highlights the importance of zinc-regulated gene expression. Mechanisms elucidated in bacteria and yeast provide examples of different possible modes of zinc-sensitive gene regulation, involving the zinc-regulated binding of transcriptional activators and repressors to gene promoter regions. A mammalian transcriptional regulatory mechanism that mediates zinc-induced transcriptional up-regulation, involving the transcription factor MTF1 (metal-response element-binding transcription factor 1), has been studied extensively. Gene responses in the opposite direction (reduced mRNA levels in response to increased zinc availability) have been observed in mammalian cells, but a specific transcriptional regulatory process responsible for such a response has yet to be identified. Examples of single zinc-sensitive transcription factors regulating gene expression in opposite directions are emerging. Although zinc-induced transcriptional repression by MTF1 is a possible explanation in some specific instances, such a mechanism cannot account for repression by zinc of all mammalian genes that show this mode of regulation, indicating the existence of as yet uncharacterized mechanisms of zinc-regulated transcription in mammalian cells. In addition, recent findings reveal a role for effects of zinc on mRNA stability in the regulation of specific zinc transporters. Our studies on the regulation of the human gene SLC30A5 (solute carrier 30A5), which codes for the zinc transporter ZnT5, have revealed that this gene provides a model system by which to study both zinc-induced transcriptional down-regulation and zinc-regulated mRNA stabilization.

scholarly journals A natural sequence consisting of overlapping glucocorticoid-responsive elements mediates glucocorticoid, but not androgen, regulation of gene expression

2000 ◽  
Vol 350 (1) ◽  
pp. 123-129 ◽  
Author(s):  
Charbel MASSAAD ◽  
Michèle GARLATTI ◽  
Elizabeth M. WILSON ◽  
Françoise CADEPOND ◽  
Robert BAROUKI
Keyword(s):  
Gene Expression ◽  
Thymidine Kinase ◽  
Transcriptional Activation ◽  
Regulation Of Gene Expression ◽  
Gene Promoter ◽  
Mobility Shift ◽  
Liver And Kidney ◽  
Androgen Regulation ◽  
Responsive Element ◽  
Half Site

Cytosolic aspartate aminotransferase (cAspAT) is regulated by glucocorticoids in rat liver and kidney. Part of this regulation is mediated by an unusual glucocorticoid-responsive element (GRE)-like sequence called GRE A. GRE A is composed of two overlapping imperfect GREs, each comprising a conserved half-site (half-sites 1 and 4 respectively) and a poorly conserved half-site (half-sites 2 and 3 respectively). The sequence binds co-operatively two dimers of the glucocorticoid receptor (GR) and mediates efficient glucocorticoid regulation of gene expression. Analysis of deletions of the cAspAT gene promoter and subcloning of GRE A upstream of the thymidine kinase promoter indicate that this sequence is responsive to glucocorticoids, but not to androgens. Electrophoretic mobility shift assays indicate that the GRE A unit does not bind the androgen receptor (AR). The modification of three nucleotides in the poorly conserved half-sites 2 and 3, converting GRE A into two overlapping high-affinity GREs (ov-cGRE), resulted in co-operative binding of the AR. Furthermore, ov-cGRE efficiently mediated androgen regulation of the thymidine kinase promoter. A single base modification in half-site 2 or 3 in GRE A allowed the binding of the AR as one or two dimers respectively, and restored transcriptional activation by androgens only in the latter case. Thus the poor affinity of the AR for half-sites 2 and 3 prevented its binding to GRE A, indicating that the overlapping GRE A sequence of the cAspAT gene promoter discriminates a glucocorticoid-mediated from an androgen-mediated response.

Structure and ovarian expression of the oxytocin gene in sheep

1990 ◽  
Vol 2 (6) ◽  
pp. 703 ◽  
Author(s):  
R Ivell ◽  
N Hunt ◽  
N Abend ◽  
B Brackman ◽  
D Nollmeyer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Corpus Luteum ◽  
Gene Promoter ◽  
Oestrous Cycle ◽  
Promoter Regions ◽  
Low Levels

In sheep, the oxytocin gene is highly up-regulated in the ovarian corpus luteum as well as in the hypothalamus. This expression is already elevated on Day 2 of the oestrous cycle, representing 1% of all transcripts in this tissue, and it declines thereafter to low levels after Day 6 of the cycle. In order to study the mechanisms involved in luteal oxytocin gene expression, we have cloned and sequenced the oxytocin gene from the sheep. This gene is closely homologous to other known mammalian oxytocin genes, especially the bovine one, and comparison of the gene promoter regions highlights several blocks of putative control elements.

scholarly journals PfGCN5-Mediated Histone H3 Acetylation Plays a Key Role in Gene Expression in Plasmodium falciparum

2007 ◽  
Vol 6 (7) ◽  
pp. 1219-1227 ◽  
Author(s):  
Long Cui ◽  
Jun Miao ◽  
Tetsuya Furuya ◽  
Xinyi Li ◽  
Xin-zhuan Su ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Histone Acetylation ◽  
Transcriptional Activation ◽  
Histone H3 ◽  
Epigenetic Mechanism ◽  
Promoter Regions ◽  
Specific Expression ◽  
Transcriptional Initiation ◽  
Translational Start

ABSTRACT Histone acetylation, regulated by the opposing actions of histone acetyltransferases (HATs) and deacetylases, is an important epigenetic mechanism in eukaryotic transcription. Although an acetyltransferase (PfGCN5) has been shown to preferentially acetylate histone H3 at K9 and K14 in Plasmodium falciparum, the scale of histone acetylation in the parasite genome and its role in transcriptional activation are essentially unknown. Using chromatin immunoprecipitation (ChIP) and DNA microarray, we mapped the global distribution of PfGCN5, histone H3K9 acetylation (H3K9ac) and trimethylation (H3K9m3) in the P. falciparum genome. While the chromosomal distributions of H3K9ac and PfGCN5 were similar, they are radically different from that of H3K9m3. In addition, there was a positive, though weak correlation between relative occupancy of H3K9ac on individual genes and the levels of gene expression, which was inversely proportional to the distance of array elements from the putative translational start codons. In contrast, H3K9m3 was negatively correlated with gene expression. Furthermore, detailed mapping of H3K9ac for selected genes using ChIP and real-time PCR in three erythrocytic stages detected stage-specific peak H3K9ac enrichment at the putative transcriptional initiation sites, corresponding to stage-specific expression of these genes. These data are consistent with H3K9ac and H3K9m3 as epigenetic markers of active and silent genes, respectively. We also showed that treatment with a PfGCN5 inhibitor led to reduced promoter H3K9ac and gene expression. Collectively, these results suggest that PfGCN5 is recruited to the promoter regions of genes to mediate histone acetylation and activate gene expression in P. falciparum.

scholarly journals Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1013-1021 ◽  
Author(s):  
Danxin Wang ◽  
Huizi Chen ◽  
Kathryn M. Momary ◽  
Larisa H. Cavallari ◽  
Julie A. Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Warfarin Dose ◽  
Candidate Snps ◽  
Promoter Regions ◽  
Dose Requirement ◽  
Genotype Effect ◽  
Warfarin Dose Requirement ◽  
Warfarin Dosing

Abstract Warfarin dose requirements have been associated with 2 main haplotypes in VKORC1, but the responsible polymorphisms remain unknown. To search for regulatory polymorphisms, we measured allelic mRNA expression of VKORC1 in human liver, heart, and B lymphocytes. The observed 2-fold allelic mRNA expression imbalance narrowed possible candidate SNPs to −1639G>A and 1173C<T. This genotype effect was observed selectively in the liver but not in heart or lymphocytes. In vitro expression of VKORC1 gene constructs, including coding and promoter regions, failed to reveal any genotype effect on transcription and mRNA processing. Chromatin immunoprecipitation with antibodies against acetyl-histone3 and K4-trimethyl-histone3 revealed preferential association of the promoter −1639 G allele with active chromatin, consistent with enhanced mRNA expression. The minor −1639 A allele generates a suppressor E-box binding site, apparently regulating gene expression by a mechanism undetectable with reporter gene assays. A clinical association study demonstrated that promoter SNP −1639G>A, and the tightly linked intron1 SNP 1173C>T, predict warfarin dose more accurately than intron 2 SNP 1542G>C in blacks. Increased warfarin dose requirement in blacks was accounted for by lower frequency of the −1639 A allele. Therefore, −1639G>A is a suitable biomarker for warfarin dosing across ethnic populations.

scholarly journals 8-OxoG in GC-rich Sp1 binding sites enhances gene transcription during adipose tissue development in juvenile mice

2019 ◽  
Author(s):  
Jong Woo Park ◽  
Young In Han ◽  
Tae Min Kim ◽  
Su Cheong Yeom ◽  
Jaeku Kang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Adipose Tissue ◽  
Binding Sites ◽  
Gene Promoter ◽  
Tissue Development ◽  
Promoter Regions ◽  
Dna Lesion ◽  
Estrogen Response ◽  
Adipose Tissue Development

ABSTRACTThe oxidation of guanine to 8-oxoguanine (8-oxoG) is the most common type of oxidative DNA lesion. There is a growing body of evidence indicating that 8-oxoG is not only pre-mutagenic, but also plays an essential role in modulating gene expression along with its cognate repair proteins. In this study, we investigated the relationship between 8-oxoG formed under intrinsic oxidative stress conditions and gene expression in adipose and lung tissues of juvenile mice. We observed that transcriptional activity and the number of active genes were significantly correlated with the distribution of 8-oxoG in gene promoter regions, as determined by reverse-phase liquid chromatography/mass spectrometry (RP-LC/MS), and 8-oxoG and RNA sequencing. Gene regulation by 8-oxoG was not associated with the degree of 8-oxoG formation. Instead, genes with GC-rich transcription factor binding sites in their promoters became more active with increasing 8-oxoG abundance as also demonstrated by specificity protein 1 (Sp1)- and estrogen response element (ERE)-luciferase assays in human embryonic kidney (HEK293T) cells. These results indicate that the occurrence of 8-oxoG in GC-rich Sp1 binding sites is important for gene regulation during adipose tissue development.

scholarly journals 8-OxoG in GC-rich Sp1 binding sites enhances gene transcription in adipose tissue of juvenile mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jong Woo Park ◽  
Young In Han ◽  
Sung Woo Kim ◽  
Tae Min Kim ◽  
Su Cheong Yeom ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Adipose Tissue ◽  
Binding Sites ◽  
Gene Promoter ◽  
Promoter Regions ◽  
Dna Lesion ◽  
Estrogen Response ◽  
Adipose Tissue Development ◽  
Specificity Protein

Abstract The oxidation of guanine to 8-oxoguanine (8-oxoG) is the most common type of oxidative DNA lesion. There is a growing body of evidence indicating that 8-oxoG is not only pre-mutagenic, but also plays an essential role in modulating gene expression along with its cognate repair proteins. In this study, we investigated the relationship between 8-oxoG formed under intrinsic oxidative stress conditions and gene expression in adipose and lung tissues of juvenile mice. We observed that transcriptional activity and the number of active genes were significantly correlated with the distribution of 8-oxoG in gene promoter regions, as determined by reverse-phase liquid chromatography/mass spectrometry (RP-LC/MS), and 8-oxoG and RNA sequencing. Gene regulation by 8-oxoG was not associated with the degree of 8-oxoG formation. Instead, genes with GC-rich transcription factor binding sites in their promoters became more active with increasing 8-oxoG abundance as also demonstrated by specificity protein 1 (Sp1)- and estrogen response element (ERE)-luciferase assays in human embryonic kidney (HEK293T) cells. These results indicate that the occurrence of 8-oxoG in GC-rich Sp1 binding sites is important for gene regulation during adipose tissue development.

scholarly journals Sequential Action of Ets-1 and Sp1 in the Activation of the Human β-1,4-Galactosyltransferase V Gene Involved in Abnormal Glycosylation Characteristic of Cancer Cells

2007 ◽  
Vol 282 (38) ◽  
pp. 27702-27712 ◽  
Author(s):  
Takeshi Sato ◽  
Kiyoshi Furukawa
Keyword(s):  
Gene Expression ◽  
Binding Site ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Promoter Activity ◽  
A549 Cells ◽  
Gene Promoter ◽  
Dominant Negative ◽  
Mobility Shift ◽  
V Gene

Malignant transformation is associated with increased gene expression of β-1,4-galactosyltransferase (β-1,4-GalT) V, which contributes to the biosynthesis of highly branched N-linked oligosaccharides characteristic of cancer cells. Our previous study showed that expression of the human β-1,4-GalT V gene is regulated by Sp1 (Sato, T., and Furukawa, K. (2004) J. Biol. Chem. 279, 39574–39583), and a subsequent study showed that the gene expression is also activated by Ets-1, a product of the oncogene (Sato, T., and Furukawa, K. (2005) Glycoconj. J. 22, 365). Herein we report the mechanism of β-1,4-GalT V gene activation by these transcription factors. The gene expression and promoter activity of β-1,4-GalT V increased when the ets-1 cDNA was transfected into A549 cells, which contain a small amount of Ets-1, but decreased dramatically when the dominant-negative ets-1 cDNA was transfected into HepG2 cells, which contain a large amount of Ets-1. Luciferase assays using deletion constructs of the β-1,4-GalT V gene promoter showed that promoter region –116 to +22 is critical for the transcriptional activation of the gene by Ets-1. Despite the presence of one Ets-1-binding site, which overlapped the Sp1-binding site, electrophoretic mobility shift assays showed that the region bound preferentially to Sp1 rather than to Ets-1. To solve this problem, we examined the transcriptional regulation of the human Sp1 gene by Ets-1 and found that the gene expression and promoter activity of Sp1 are regulated by Ets-1 in cancer cells. Functional analyses of two Ets-1-binding sites in the Sp1 gene promoter showed that only Ets-1-binding site –413 to –404 is involved in the activation of the gene by Ets-1. These results indicate that Ets-1 enhances expression of the β-1,4-GalT V gene through activation of the Sp1 gene in cancer cells.

Interleukin-15 induces IL-12 receptor β1 gene expression through PU.1 and IRF 3 by targeting chromatin remodeling

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 711-720 ◽  
Author(s):  
Tipayaratn Musikacharoen ◽  
Asako Oguma ◽  
Yasunobu Yoshikai ◽  
Norika Chiba ◽  
Akio Masuda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Transcriptional Activation ◽  
Transcriptional Start Site ◽  
Regulatory Region ◽  
Gene Promoter ◽  
Interferon Γ ◽  
Interleukin 12 ◽  
Promoter Activation ◽  
Ifn Γ

AbstractInterleukin-12 receptor β1 (IL12RB1) is expressed on a variety of immune cells, including T and natural killer (NK) cells and macrophages, and is involved in innate and adaptive immune responses. Levels of IL12RB1 mRNA are dynamically regulated by various cytokines, including interferon-γ (IFN-γ) and IL-15. To reveal the regulatory mechanisms governing IL12RB1 gene expression, we analyzed the transcriptional regulatory region of the mouse IL12RB1 gene. Promoter analyses in a mouse macrophage cell line, RAW264.7, revealed that the 2508-bp region upstream of the transcriptional start site is sufficient for the full transcriptional activation of the IL12RB1 gene by IFN-γ or IL-15. Analyses of the deletion mutants revealed critical roles of IRE/ISRE and ETS/PU.1 elements, to which IRF3 and PU.1, respectively, bound. Notably, chromatin immunoprecipitation (ChIP) assays revealed IL-15 rapidly induced histone H3 acetylation at the IL12RB1 promoter. Consistently, IL-15, as a histone deacetylase inhibitor, synergistically enhanced IL12RB1 gene expression and promoter activation by IFN-γ through increased protein binding to ETS/PU.1 and IRE/ISRE sites. Additionally, IL12RB1 promoter activation by IFN-γ was enhanced by the coexpression of a coactivator protein, CBP. Thus, IL-15 induces chromatin remodeling of the IL12RB1 gene promoter, increasing IL12RB1 mRNA expression in synergy with IFN-γ through the recruitment of PU.1 and IRF3.

scholarly journals Nonparametric Tests for Differential Histone Enrichment with ChIP-Seq Data

2015 ◽  
Vol 14s1 ◽  
pp. CIN.S13972 ◽  
Author(s):  
Qian Wu ◽  
Kyoung-Jae Won ◽  
Hongzhe Li
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Binding Sites ◽  
Negative Binomial ◽  
Kernel Smoothing ◽  
Gene Promoter ◽  
Nonparametric Tests ◽  
Promoter Regions ◽  
Experimental Conditions ◽  
Nonparametric Hypothesis Testing

Chromatin immunoprecipitation sequencing (ChIP-seq) is a powerful method for analyzing protein interactions with DNA. It can be applied to identify the binding sites of transcription factors (TFs) and genomic landscape of histone modification marks (HMs). Previous research has largely focused on developing peak-calling procedures to detect the binding sites for TFs. However, these procedures may fail when applied to ChIP-seq data of HMs, which have diffuse signals and multiple local peaks. In addition, it is important to identify genes with differential histone enrichment regions between two experimental conditions, such as different cellular states or different time points. Parametric methods based on Poisson/negative binomial distribution have been proposed to address this differential enrichment problem and most of these methods require biological replications. However, many ChIP-seq data usually have a few or even no replicates. We propose a nonparametric method to identify the genes with differential histone enrichment regions even without replicates. Our method is based on nonparametric hypothesis testing and kernel smoothing in order to capture the spatial differences in histone-enriched profiles. We demonstrate the method using ChIP-seq data on a comparative epigenomic profiling of adipogenesis of murine adipose stromal cells and the Encyclopedia of DNA Elements (ENCODE) ChIP-seq data. Our method identifies many genes with differential H3K27ac histone enrichment profiles at gene promoter regions between proliferating preadipocytes and mature adipocytes in murine 3T3-L1 cells. The test statistics also correlate with the gene expression changes well and are predictive to gene expression changes, indicating that the identified differentially enriched regions are indeed biologically meaningful.

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