Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation

Abstract

Angelman syndrome (AS) is a human neurological disorder caused by lack of maternal UBE3A expression in the brain. UBE3A is known to function as both an ubiquitin-protein ligase (E3) and a coactivator for steroid receptors. Many ubiquitin targets, as well as interacting partners, of UBE3A have been identified. However, the pathogenesis of AS, and how deficiency of maternal UBE3A can upset cellular homeostasis, remains vague. In this study, we performed a genome-wide microarray analysis on the maternal Ube3a-deficient (Ube3a mÀ/p+ ) AS mouse to search for genes affected in the absence of Ube3a. We observed 64 differentially expressed transcripts (7 upregulated and 57 downregulated) showing more than 1.5-fold differences in expression (Po0.05). Pathway analysis shows that these genes are implicated in three major networks associated with cell signaling, nervous system development and cell death. Using quantitative reverse-transcription PCR, we validated the differential expression of genes (Fgf7, Glra1, Mc1r, Nr4a2, Slc5a7 and Epha6) that show functional relevance to AS phenotype. We also show that the protein level of melanocortin 1 receptor (Mc1r) and nuclear receptor subfamily 4, group A, member 2 (Nr4a2) in the AS mice cerebellum is decreased relative to that of the wild-type mice. Consistent with this finding, expression of small-interfering RNA that targets Ube3a in P19 cells caused downregulation of Mc1r and Nr4a2, whereas overexpression of Ube3a results in the upregulation of Mc1r and Nr4a2. These observation help in providing insights into the genesis of neurodevelopmental phenotype of AS and highlight specific area for future research.

Ube3a/E6AP is involved in a subset of MeCP2 functions

“…3D). It was also reported that Sst transcription was down-regulated in the Ube3a mÀ/p+ cerebellum compared to wild-type mice [26]. Taken together, these data suggest that E6AP can function as a coactivator for the MeCP2-mediated regulation of Sst expression in vivo.…”

“…We next asked whether MeCP2 and E6AP could function together in regulating target gene expression, given that MeCP2 and E6AP both act as regulators of gene expression independently [10,17,26,27]. Since E6AP can act as a transcriptional coactivator [17], we tested whether E6AP acts as a coactivator for MeCP2.…”

Clinical Significance and Prognostic Value of microRNA Expression Signatures in Hepatocellular Carcinoma

“…These results show that miRNA levels detected by microarray are reliable and can be used for the further analysis. Identification of 20 miRNAs associated with survival in the training set The microarray raw data in the training set were normalized and transformed into a log 2 ratio of hepatocellular carcinoma to noncancerous liver by BRB-ArrayTools and then miRNAs with expression in less than 15% of samples and change in expression less than 1.5-fold were filtered (23,24). To identify a miRNA signature correlated with patients' survival, the relationship between miRNA expression levels and patients' survival was assessed in the training set by fitting Cox proportional hazards models using BRBArrayTools software and miRNAs were chosen by the criteria of P < 0.1.…”

` Neurodevelopmental Underpinnings of Angelman Syndrome

“…These genes are functioning in signal transduction, nervous system development and cell death. Some of those genes (Fgf7, Glra1, Mc1r, Nr4a2, Slc5a7 and Epha6) are confirmed of relevant with AS phenotype [49]. It was also shown that elevated Arc level in AS mouse disturbs the brain-derived neurotrophic factor (BDNF) to recruit the postsynaptic density-95 (PSD-95) protein, disrupts association of PSD-95 with TrkB, and the association of PLCγ and Grb2-associated binder 1 (Gab1) with TrkB, therefore impairing BDNF, TrkB and PI3K-Akt pathways [57].…”

“…It was reported that the post mitotic neonatal neurons are decreased after maternal Ube3a inactivation in AS mouse hippocampus [48]. The loss of neurons may be due to either impaired metabolism or the disturbance of genes involved in cell death process [49], or both. It was also shown that mitochondria in AS mouse exhibited a smaller size in the hippocampus and a partial oxidative phosphorylation defect in the whole brain [22].…”