Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptome comparison between CHOPS syndrome and Cornelia de Lange syndrome

ABSTRACT: CHOPS syndrome is caused by germline gain-of-function mutations of AFF4. Cornelia de Lange syndrome is caused by germline mutations of cohesin loading factors or cohesin complex genes such as NIPBL, SMC1A, SMC3 and HDAC8. There are many overlapping clinical features exist between CHOPS syndrome and Cornelia de Lange syndrome. To identified commonly dysregulated genes in CHOPS syndrome and Cornelia de Lange syndrome, we perfomred side-by-side transcriptome comparison between CHOPS syndrome and Cornelia de Lange syndrome. In this transcriptome analysis, patient derived skin fibroblasts from two CHOPS syndrome probands, two Cornelia de Lange syndrome probands, and four age-gender-ethnicity matched healthy control subjects were used.The samples used for Human Gene 2.0 arrays are two CHOPs syndrome samples (CDL160 and CDL444), two Cornelia de Lange syndrome samples (CdL006: 7 year-old Caucasian female NIPBL 742_743delCT ;L248TfsX6 and CdL015: 10 year-old Caucasian male NIPBL 2969delG;G990DfsX2), and four age gender matched control samples (GM01652, GM01864, GM02036 and GM03348).

ORGANISM(S): Homo sapiens

SUBMITTER: IAN KRANTZ

PROVIDER: E-GEOD-64034 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The Cohesin apparatus has a canonical role in sister chromatid cohesion. Heterozygous mutations in Nipped B-like (NIPBL), SMC1A, and SMC3 have been found in 60% of probands with Cornelia de Lange Syndrome (CdLS), a dominant multi-system genetic disorder with variable expression. We have performed a genome-wide transcription assessment as well as cohesin binding analysis using human lymphoblastoid cell lines (LCLs) from probands with CdLS and controls. Here, we report a unique profile of genes dysregulated in CdLS that correlates with different clinical presentations. Genome-wide analysis of cohesin binding demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of an insulator. However, the binding sites are enriched within the promoter regions of the dysregulated genes and are significantly decreased in CdLS probands, indicating an alternative role of cohesin as a classic transcription factor. Cohesin also co-localizes with CTCF at the boundary elements affecting neighboring gene expression in CdLS probands. We propose that the CdLS phenotype is the result of dysregulated gene expression rather than defective sister chromatid cohesion. Phenotype specific expression profiles are also described. Experiment Overall Design: To identify differentially expressed genes between CdLS patients and controls, age and gender matched samples from 16 normal Caucasian controls and 17 clinical severely affected Caucasian patients with NIPBL protein truncating mutations (nonsense or frameshift) were chosen as the training set for the discriminate analysis. To validate the expression pattern obtained from the training set, 6 samples including 1 healthy control, 1 Egyptian CdLS patient, 2 Roberts syndrome patients, and 2 Alagille patients were used as the testing set. All the 39 cell lines were growing anonymously and the processing of these 39 cell lines were randomized by genotypes to eliminate batch effects that may contribute to genotype-specific gene expression

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Transcriptome comparison between CHOPS syndrome and Cornelia de Lange syndrome

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