Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Human Developmental Biology Resource (HDBR) expression resource-RNAseq

ABSTRACT: The Human Developmental Biology Resource (HDBR) expression resource is a new resource for studying prenatal human brain development. It consists of two parts which have been uploaded as two submissions: HDBR expression resource- RNAseq (E-MTAB-4840, this submission) and HDBR expression resource- SNP data (E-MTAB-4843). It is unique in the age range (4 post conception weeks [PCW] to 17PCW) and number of brains studied, particularly those under 8PCW. It is also unique in that both the large-scale data sets and the corresponding RNA and DNA samples are available, the latter via the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR; http://www.hdbr.org). There are 628 RNA-seq datasets from different regions of the brains studied. The number of regions depends on the stage and size of the sample and/or the tissue available. Embryos (4-8PCW) have been staged using a modified Carnegie staging system, details can be found at http://database.hudsen.eu/. All the RNAseq datasets from the same brain have the same embryo/fetus number (e.g. RNAseq datasets HDBR251-HDBR254 are from different tissues from embryo number 1406). The embryo/fetus ID number is recorded in the individual column. The majority of the brains studied are between 4 and 12PCW. During this time the major brain regions are established and there are the early stages of cortex development. DNA was prepared from all the tissues used for RNA-seq analysis and SNP genotype data generated from one tissue from each brain. RNA-seq data and SNP-data from the same tissue and brain have the same name (e.g. HDBR469). There are also SNP genotype data from 229 additional specimens in paraffin wax blocks available for individual gene expression studies. These data are in the accompanying HDBR expression resource- SNP data (E-MTAB-4843).

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Susan Lindsay

PROVIDER: E-MTAB-4840 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:CDK8 (cyclin-dependent kinase 8) is a kinase component of a multi - protein Mediator complex, involved in transcription control. Several studies indicated that high overexpression and activity of CDK8 could be a driver of malignant progression in colorectal cancer (CRC). Herewith we present molecular insights into mechanism of action of SEL120-34A - a selective small molecule inhibitor of CDK8 kinase. Biochemical and binding studies indicated that SEL120-34A selectively binds and inhibits enzymatic activity of CDK8 in the low nM range. Recently CDK8 has been described as a regulator of STAT1 activity in NK cells where by phosphorylating STAT1 serine 727 (Ser727) influences a possible immunoescape mechanism in various cancers. Consistently, SEL120-34A and other recently reported selective CDK8 inhibitors could repress phosphorylation of STAT1 at a Ser727 at low nM concentrations in cancer cells without any significant changes on tyrosine sites directly regulated by JAK kinases. SEL120-34A inhibited expression of several STAT1 dependent genes in CRC cell lines, stimulated by various cytokines and growth factors. These results were further corroborated with specific CDK8 siRNA knockdown experiments and chromatin immunoprecipitation studies showing CDK8 occupancy on promoters of SEL120-34A regulated genes. In order to better characterize in vivo mechanism of action, mice bearing HCT116 and Colo205 xenograft tumors were treated with SEL120-34A and gene expression changes were measured with microarrays in excised tumors. In animals treated with the CDK8 inhibitor a dose dependent repression of STAT1 Ser727 was observed. The functional analyses of significantly (adj. p. value < 0.05) altered genes with Gene Ontology revealed that those with reduced expression belong to interferon I pathway and type I interferon-mediated signaling pathway terms. This subset of STAT regulated genes was further characterized as an interferon-related DNA damage resistance signature (IRDS) - a prosurvival pathway which correlated strongly with resistance to radiation and chemotherapy in various tumors. Consistently, SEL120-34A has shown very potent cytotoxic synergy with standard of care drugs in CRC, particularly in cells stimulated with interferons. Taken together, for the first time we have shown that selective CDK8 inhibitors are potent regulators of STAT related - IRDS signaling pathway in vitro and in vivo. In addition to previously reported stand-alone efficacy of CDK8 inhibitors in vivo, we provide also a combination treatment rationale for CRC. Female mice, SCID beige , 7-8 weeks old, were maintained according to the standards of the specific pathogen free conditions. Colo205 or HCT116 cells were centrifuged at 1000 rpm for 5 min and counted using Trypan blue method. A 5M cells were suspended in PBS and MatrigelÂ® (BD Biosciences) (3:1, v:v) and were injected subcutaneously (SC), on the right hind limb. As the tumor was maintained until it reached ~100-150 mm3. Mice were randomized into uniform groups and subjected to the compound administrations. Prior to use, compound was dissolved freshly in water and administered 30mg/kg BIDx3 per os using cannula in a volume of 10 ul per 1 g of body weight. Tumor samples were collected 4 and 16 hours after last compound dose and preserved in RNAlater.

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Human Developmental Biology Resource (HDBR) expression resource-RNAseq

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