Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of peripheral blood or primary finroblast cultures from choroideremia patients to determine if loss-of-function mutations in REP-1 affect intracellular vesicle transport in fibroblasts and monocytes of CHM patients

ABSTRACT: Choroideremia (CHM) is a progressive X-linked retinopathy caused by mutations in the CHM gene, which encodes Rab escort protein-1 (REP-1), an escort protein involved in the prenylation of Rabs. Under-prenylation of certain Rabs, as a result of loss of function mutations in REP-1, could affect vesicular trafficking, exocytosis and secretion. To evaluate this hypothesis, intracellular vesicle transport, lysosomal acidification and rates of proteolytic degradation were studied in monocytes (CD14+ fraction) and primary skin fibroblasts from the nine age-matched controls and thirteen CHM patients carrying 10 different loss-of-function mutations. expression data were collected from 6 CHM patients' monocytes and 4 CHM primary fibroblasts cultures, monocytes or FB from 5 normal age-matched subjects were used as a control

ORGANISM(S): Homo sapiens

SUBMITTER: Jennifer Barb

PROVIDER: E-GEOD-17549 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Loss-of-function mutations in Rab escort protein 1 (REP-1) affect intracellular transport in fibroblasts and monocytes of choroideremia patients.

Strunnikova Natalia V NV Barb Jennifer J Sergeev Yuri V YV Thiagarajasubramanian Ashwin A Silvin Christopher C Munson Peter J PJ Macdonald Ian M IM

PloS one 20091222 12

<h4>Background</h4>Choroideremia (CHM) is a progressive X-linked retinopathy caused by mutations in the CHM gene, which encodes Rab escort protein-1 (REP-1), an escort protein involved in the prenylation of Rabs. Under-prenylation of certain Rabs, as a result of loss of function mutations in REP-1, could affect vesicular trafficking, exocytosis and secretion in peripheral cells of CHM patients.<h4>Methodology/principal findings</h4>To evaluate this hypothesis, intracellular vesicle transport, ly ...[more]

PMID: 20027300

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Project description:Transcriptional silencing of terminal differentiation genes by the Polycomb group (PcG) machinery is emerging as a key feature of precursor cells in stem cell lineages. How, then, is this epigenetic silencing reversed for proper cellular differentiation? Here we investigate how the developmental program reverses local PcG action to allow expression of terminal differentiation genes in the Drosophila male germline stem cell lineage. We find that the silenced state, set up in precursor cells, is relieved through developmentally regulated sequential events at promoters once cells commit to spermatocyte differentiation. The programmed events include global down-regulation of PRC2, recruitment of hypophosphorylated RNA Polymerase II (Pol II) to promoters, as well as expression and action of cell-type specific homologs of subunits of TFIID (tTAFs). In addition, action of tMAC, a tissue specific version of the MIP/dREAM complex, is required both for recruitment of tTAFs to target differentiation genes and for proper cell-type specific localization of PRC1 components and tTAFs to the spermatocyte nucleolus. Together, action of the tMAC and tTAF cell-type specific chromatin and transcription machinery leads to loss of Polycomb and release of Pol II from the promoter of terminal differentiation genes to elongation, allowing robust transcription of the terminal differentiation genes. Total RNA from approximately 200 pairs of fly testes (bam1/bam-delta-86; aly2/aly5P; sa1/sa2; y,w) was extracted using TRIzol (Invitrogen, #15596-018, Carlsbad, CA, USA) following the manufacturer's instructions. The genomic DNA was degraded using 2 Units of DNase I (Fermentas, #EN0521, Glen Burnie, MD, USA) at 37 degreeC for 20 minutes. RNA integrity was checked by gel electrophoresis (1% agarose). Approximately 4 ≈í¬∫g of total RNA from each biological replicate were used to generate labeling probes to hybridize with the Affymetix GeneChip Drosophila Genome 2.0 Array according to the Affymetrix protocol. Three biological replicates were performed for each genotype. Microarray hybridization was processed at the Core Facility at the Stanford University School of Medicine and the raw data were exported from the Affymetrix Microarray Suite (MAS). The CEL files were used for signal normalization with RMA as part of the limma package from the Bioconductor R packages (http://www.bioconductor.org).

Dataset Information

Transcription profiling of peripheral blood or primary finroblast cultures from choroideremia patients to determine if loss-of-function mutations in REP-1 affect intracellular vesicle transport in fibroblasts and monocytes of CHM patients

Publications

Loss-of-function mutations in Rab escort protein 1 (REP-1) affect intracellular transport in fibroblasts and monocytes of choroideremia patients.

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