Blood expression profiles of fragile X premutation carriers identify genes involved in neurodegenerative and infertility phenotypes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Elisabet Mateu Huertas
PROVIDER: E-GEOD-48903 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Fragile X premutation carriers (fXPC) of the CGG expansion in the 5M-bM-^@M-^Y-UTR of the fragile X mental retardation 1 (FMR1) gene are at high risk of Fragile X Tremor/Ataxia Syndrome (FXTAS), and females might undergo Premature Ovarian Failure (POF1). We have evaluated the peripheral blood gene expression profiles of fXPC and detected a strong deregulation of genes enriched in FXTAS-relevant biological pathways, including inflammation, and neuronal homeostasis and survival. More than 30% of differentially expressed correspond to long non-coding RNAs (lncRNAs). Several deregulated genes (CASP3, DFFA, APP, AKT1, COX6C, COX7B, SOD1, RNF10, HDAC5, ATXN7, ATXN3 and EAP1) were validated in brain samples of a mouse model of FXTAS and in neuronal cells expressing the expanded FMR1 5M-bM-^@M-^Y-UTR. One of the validated genes is the early at menopause 1 (EAP1) gene. We confirmed the EAP1 deregulation both in male and female fXPC. Down-regulation was stronger in female fXPC with POF1 compared with female fXPC without POF1. Increased levels of FMR1 mRNA were detected in all brain areas of the CGG-KI mouse model. EAP1 was significantly downregulated in the brainstem and cerebellum of the KI mouse, suggesting that EAP1 levels in certain brain areas could contribute to POF in this model. All together, these results suggest that gene expression profiling in blood of fXPC reflects changes in the brain transcriptome that may underlie neuropathological aspects in FXTAS and of POF. In the study presented here, we have 6 biological replicats for the Mock conditions, 6 biological replicates for the expression of the wild type FMR1 5'UTR, 6 biological replicates for the expression of the mutant FMR1 5'UTR and 6 biological replicates for the overexpression of the muatnt FMR1 5'UTR.
2014-02-20 | E-GEOD-48902 | biostudies-arrayexpress
Project description:Fragile X premutation carriers (fXPC) of the CGG expansion in the 5M-bM-^@M-^Y-UTR of the fragile X mental retardation 1 (FMR1) gene are at high risk of Fragile X Tremor/Ataxia Syndrome (FXTAS), and females might undergo Premature Ovarian Failure (POF1). We have evaluated the peripheral blood gene expression profiles of fXPC and detected a strong deregulation of genes enriched in FXTAS-relevant biological pathways, including inflammation, and neuronal homeostasis and survival. More than 30% of differentially expressed correspond to long non-coding RNAs (lncRNAs). Several deregulated genes (CASP3, DFFA, APP, AKT1, COX6C, COX7B, SOD1, RNF10, HDAC5, ATXN7, ATXN3 and EAP1) were validated in brain samples of a mouse model of FXTAS and in neuronal cells expressing the expanded FMR1 5M-bM-^@M-^Y-UTR. One of the validated genes is the early at menopause 1 (EAP1) gene. We confirmed the EAP1 deregulation both in male and female fXPC. Down-regulation was stronger in female fXPC with POF1 compared with female fXPC without POF1. Increased levels of FMR1 mRNA were detected in all brain areas of the CGG-KI mouse model. EAP1 was significantly downregulated in the brainstem and cerebellum of the KI mouse, suggesting that EAP1 levels in certain brain areas could contribute to POF in this model. All together, these results suggest that gene expression profiling in blood of fXPC reflects changes in the brain transcriptome that may underlie neuropathological aspects in FXTAS and of POF. In the study presented here, we have 5 control samples plus one biological replicate and 9 patients with CGG expansions in the 5'UTR of the FMR1 gene (being premutation carriers)
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2014-04-01 | E-GEOD-55127 | biostudies-arrayexpress
Project description:C/EBPM-NM-1 induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem cells (iPSCs) when co-expressed with Oct4, Sox2, Klf4 and Myc (OSKM). However, how C/EBPM-NM-1 accomplishes these effects is unclear. We now found that transient C/EBPM-NM-1 expression followed by OSKM activation induces a 100 fold increase in iPSC reprogramming efficiency, involving 95% of the cells. During this conversion pluripotency and epithelial-mesenchymal transition genes become dramatically up-regulated and 60% of the cells express Oct4 within 2 days. C/EBPM-NM-1 acts as a pathbreaker since it transiently makes the chromatin of pluripotency genes more accessible to DNase I. It also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated following OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKMM-bM-^@M-^Pinduced B cell reprogramming. Since the enzyme is also required for efficient C/EBPM-NM-1-induced immune cell conversion, our data suggest that Tet2 provides a mechanistic link between iPSC reprogramming and B cell transdifferentiation. The rapid iPS reprogramming approach described should help to fully elucidate the process and has potential clinical applications. Refer to individual Series
2013-11-17 | E-GEOD-52397 | biostudies-arrayexpress
Project description:Adult renal stem/progenitor cells (ARPCs), first identified in the BowmanM-bM-^@M-^Ys capsule, were recently identified also in the tubular compartment and it was demonstrated that renal progenitors from both locations were positive for PAX-2, CD133 and CD24 and exhibited multipotent differentiation ability. Recent studies indicated that microRNAs (miRNAs), a class of noncoding small RNAs that participate in the regulation of gene expression, may play a key role in stem cell self-renewal and differentiation. Distinct sets of miRNAs are specifically expressed in pluripotent stem cells but not in adult tissues, suggesting a role for miRNAs in stem cell self-renewal. We compared miRNA expression profiles of renal progenitors with that of renal proximal tubular cells (RPTECs) and of mesenchymal stem cells (MSC) and found distinct sets of miRNAs that were specifically expressed both in tubular and glomerular ARPCs. In particular, the miR-1915 and miR-1225-5p regulated the expression of important markers of renal progenitors, such as CD133 and PAX-2, and important genes involved in the repair mechanisms of ARPCs, such as TLR2. We demonstrated that the expression of both the renal stem cell markers CD133 and PAX-2 depends, at least in part, on lower miR-1915 levels and showed that the increase of miR-1915 levels improved capacity of ARPCs to differentiate into adipocyte-like and epithelial-like cells. Finally, we found that the low levels of miR-1225-5p were responsible for high TLR2 expression in ARPCs. Therefore, together, the miR-1915 and the miR-1225-5p seems to regulate important trait of ARPCs: the stemness and the repair capacity. Sixteen samples consisting of 5 glomerular and tubular ARPCs each, 3 MSCs, and 3 RPTECS.
2013-05-30 | E-GEOD-42391 | biostudies-arrayexpress
Project description:The 2.2 Mb long dystrophin (DMD) gene, the largest gene in the human genome, corresponds to roughly 0.1% of the entire human DNA sequence. Mutations in this gene cause Duchenne muscular dystrophy and other milder X-linked, recessive dystrophinopathies. Using a custom-made tiling array, specifically designed for the DMD locus, we identified a variety of novel long non-coding RNAs (ncRNAs), both sense and antisense oriented, whose expression profiles mirror that of DMD gene. Importantly, these transcripts are intronic in origin and specifically localized to the nucleus and are transcribed contextually with dystrophin isoforms or primed by MyoD-induced myogenic differentiation. Furthermore, their forced ectopic expression in both human muscle and neuronal cells causes a specific and negative regulation of endogenous dystrophin full length isoforms and significantly down-regulate the activity of a luciferase reporter construct carrying the minimal promoter regions of the muscle dystrophin isoform. Consistent with this apparently repressive role, we found that, in muscle samples of DMD symptomatic female carriers, lncRNAs expression levels inversely correlate with those of muscle full length DMD isoforms. Overall these findings unveil an unprecedented complexity of the transcriptional pattern of the DMD locus and reveal that DMD-specific lncRNAs may contribute to the orchestration and homeostasis of the muscle dystrophin expression pattern by selective targeting and down-modulation of dystrophin promoter transcriptional activity. We tiled the entire DMD gene, in both sense and antisense directions, using the web-based Agilent eArray database, Version 4.5 (Agilent Technologies), with 60-mer oligos every 66 bp of repeat-masked genome sequence. We defined probe sets for both orientations, encompassing the DMD exons, promoters, introns, predicted MiRNA (identified by PromiRII) and conserved non-coding sequences (CNSs) identified within dystrophin introns using the VISTA programme (http://genome.lbl.gov/vista/index.shtml). Two specific sets of probes were designed to cover, in both directions, the cDNA sequences of a group of control genes identified in the Gene Expression Omnibus (GEO) database http://www.ncbi.nlm.nih.gov/geo/) and expressed equally in both normal and dystrophic muscles. Each probe set was opportunely distributed and replicated several times in order to obtain two 4x44k microarrays, referred to as DMD GEx Sense and DMD GEx Antisense, respectively, able to detect transcripts in the same and opposite directions as that of DMD gene transcription. Three commercial poly A+ RNAs from normal human brain, heart and skeletal muscle tissues were utilised (Ambion). Skin poly A+ RNA was isolated from total Skin RNA (Stratagene) using the Qiagen Oligotex kit. All RNA samples were checked for purity using a ND-1000 spectrophotometer (NanoDrop Technologies), and for integrity by electrophoresis on a 2100 BioAnalyzer (Agilent Technologies). Sample labelling and hybridisation were performed according to the protocols provided by Agilent (One-Color Microarray-Based Gene Expression Analysis version 5.0.1). The array was analysed using the Agilent scanner and Feature Extraction software (v9.1).
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2012-12-31 | E-GEOD-39699 | biostudies-arrayexpress
Project description:Elucidating the genetic basis underlying the variation in hepatic gene expression is of importance to understand disease etiology and drug metabolism variances. To date, no genome-wide eQTL analysis has been conducted in the Han Chinese, the largest ethnic group in the world. We performed a genome-wide eQTL mapping in a set of Han Chinese liver tissue (n=64). Normal (non-diseased) liver tissues were previously collected from 64 Chinese donors who provided informed consent. All samples were stored frozen at -80M-bM-^DM-^C from collection until processing for RNA and DNA extraction. DNA /Total RNA of the human liver tissue samples were extracted by using the RNA/DNA Mini Kit (Qiagen, Hilden, Germany).each RNA sample were labeled and hybridized to the One-Color Agilent 60-mer Whole Human Genome Microarray (G4112F, GPL4133) at the Agilent Microarray Facility of Shanghai genomePilot Technology, Inc. The genome-wide scan was performed using the Affymetrix Genome-Wide Human SNP Array 6.0. We tested all expression traits for their associations with each of the QC passed SNPs using PLINK's assoc function for quantitative traits, which correlates allele dosage with changes in the trait.
2015-01-02 | E-GEOD-53791 | biostudies-arrayexpress
Project description:Background: UNC50 has long been recognized as a Golgi apparatus protein in yeast, and is involved in nicotinic receptor trafficking in Caenorhabditis elegans, but little is known about UNC50 gene function in human biology despite it being conserved from yeast to high eukaryotes. Objectives: We investigated the relation between UNC50 and human hepatocellular carcinoma (HCC) and the potential mechanisms underlying HCC development. Methods: UNC50 mRNA expression patterns in 12 HCC and adjacent non-cancerous tissues determined using northern blotting were confirmed by real-time PCR in another 44 paired tissues. Microarray experiments were used to screen for global effects of UNC50 knockdown in the Hep3B cell line, and were confirmed by real-time PCR, western blotting, flow cytometry, and tetrazolium assay in both UNC50 overexpression and knockdown Hep3B cells. Results: UNC50 expression levels were upregulated in HCC tissues in comparison with the adjacent non-cancerous tissues. UNC50 knockdown reduced mRNA levels of the downstream targets of the epidermal growth factor receptor (EGFR) pathway: cyclin D1 (CCND1), EGF, matrix metalloproteinase-7 (MMP7), aldose reductase-like 1 (AKR1B10), cell surfaceM-bM-^@M-^Sassociated mucin 1 (MUC1), and gastrin (GAST). Moreover, UNC50 influenced EGF, inducing cell cycle entry by affecting cell surface EGFR amounts. Conclusions: UNC50 is a potential oncogene that promotes HCC progression by affecting the EGFR pathway. To gain insight into the role UNC50 plays in HCC progression, we used microarray analyses to identify indirect evidence of UNC50 gene function via the knockdown strategy in Hep3B cells. Hep3B cells transfected with the shRNA expression plasmids shR-467, shR-554, shR-749, and shR-MOCK were purified with 1ug/ml puromycin, and the total RNA from each cell was extracted and analyzed with oligo microarrays.
2014-11-17 | E-GEOD-63322 | biostudies-arrayexpress
Project description:Functional-assay limitations are an emerging issue in characterizing human pluripotent stem cells (hPSCs). With rodent PSCs, chimera formation, using pre-implantation embryos, is the gold-standard assay of pluripotency. In hPSCs, this can only be monitored via teratoma formation or in vitro differentiation, as ethical concerns preclude generation of human-animal chimera. To circumvent this issue, we established a functional assay utilizing interspecific blastocyst injection and in vitro culture (interspecies in vitro chimera assay). The assay uses mouse pre-implantation embryos and human PSCs to make interspecies chimeras cultured in vitro to the early egg cylinder stage. When hiPSCs, both conventional and naive type, which called M-bM-^@M-^\reset cellM-bM-^@M-^], were injected into mouse embryos and cultured. The cells were never integrated into the epiblast of egg cylinder stage-embryo. These results suggest that hPSCs, including naM-CM-/ve type, are unable to form chimera with mouse embryo. Reset cells were converted from conventional human iPSC line PB004, and then compared their gene expression profile with or without transgene overexpression induced by doxycyclin treatment.
2015-03-10 | E-GEOD-66657 | biostudies-arrayexpress