Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Whole genome expression analysis of a skin biopsy from two individuals with ectodermal dysplasia features associated with hearing loss in GRHL2

ABSTRACT: Whole-genome expression microarray analysis was performed using RNA extracted from skin biopsies sampled from two related and affected individuals as well as 4 pooled, healthy controls. The hypothesis was that the downstream effects of the inherited GRHL2 missense mutation in the two siblings would be evident by enriched pathways and processess linked to the cutaneous roles of the grainyhead like-2 protein. Functional analysis of the results identified a multitude of enriched gene ontology (GO) processes, pathways, networks and disease-associated transcripts related to the function of GRHL2 in the affected individuals' samples compared to controls. Results provide important information about significantly up-regulated and down-regulated GO networks, pathways and processes involved in epithelial morphogenesis . Total RNA extracted from two skin biopsies from each of the affected individuals was compared to skin biopsies from 4 pooled, healthy controls.

ORGANISM(S): Homo sapiens

SUBMITTER: Venu Pullabhatla

PROVIDER: E-GEOD-56486 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Using a retrovirus-mediated cDNA expression cloning approach we identified the grainyhead-like 2 (GRHL2) transcription factor as novel protooncogene. Overexpression of GRHL2 in NIH3T3 cells induced striking morphological changes, an increase in cell proliferation, anchorage-independent growth, and tumor growth in vivo. By combining a microarray analysis and a phylogenetic footprinting analysis with various biochemical assays we identified the epidermal growth factor receptor family member Erbb3 as a novel GRHL2 target gene. In breast cancer cell lines, shRNA-mediated knockdown of GRHL2 expression or functional inactivation of GRHL2 using dominant-negative GRHL2 proteins induce downregulation of ERBB3 gene expression, a striking reduction in cell proliferation and morphological and phenotypical alterations characteristic of an epithelial-to-mesenchymal transition (EMT), thus implying dual roles of GRHL2 in breast carcinogenesis. Interestingly, we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc-finger-enhancer binding protein 1 (ZEB1) which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. Finally, a comprehensive immunohistochemical analysis of GRHL2 expression in primary breast cancers showed loss of GRHL2 expression at the invasive front of primary tumors. A pathophysiological relevance of GRHL2 in breast cancer metastasis is further demonstrated by our finding of a statistically significant association between loss of GRHL2 expression in primary breast cancers and lymph-node metastasis. We thus demonstrate a crucial role of GRHL2 in breast carcinogenesis. To evaluate the role of the GRHL2 transcription factor in carcinogenessis we overexpressed the human GRHL2 protein in NIH3T3 cells. Parental NIH3T3 cells do not express the orthologic protein. Alterations in genome-wide transcriptional profiles were determined by microarray analysis.

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Whole genome expression analysis of a skin biopsy from two individuals with ectodermal dysplasia features associated with hearing loss in GRHL2

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