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Gender influences monoallelic expression of ATP10A in human brain.

ABSTRACT: Human chromosome 15q11-13 and the syntenic region of mouse chromosome 7 contain multiple imprinted genes necessary for proper neurodevelopment. Due to imprinting, paternal 15q11-13 deficiencies lead to Prader-Willi syndrome (PWS) while maternal 15q11-13 deficiencies cause Angelman syndrome (AS). The mechanisms involved in parental imprinting of this locus are conserved between human and mouse, yet inconsistencies exist in reports of imprinting of the maternally expressed gene Atp10a/ATP10A. Excess maternal 15q11-13 dosage often leads to autism-spectrum disorder therefore further investigation to characterize the true imprinting status of ATP10A in humans was warranted. In this study, we examined allelic expression of ATP10A transcript in 16 control brain samples, and found that 10/16 exhibited biallelic expression while only 6/16 showed monoallelic expression. Contrary to the expectation for a maternally expressed imprinted gene, quantitative RT-PCR revealed significantly reduced ATP10A transcript in Prader-Willi syndrome brains with two maternal chromosomes due to uniparental disomy (PWS UPD). Furthermore, a PWS UPD brain sample with monoallelic ATP10A expression demonstrated that monoallelic expression can be independent of imprinting. Investigation of factors that may influence allelic ATP10A expression status revealed that gender has a major affect, as females were significantly more likely to have monoallelic ATP10A expression than males. Regulatory sequences were also examined, and a promoter polymorphism that disrupts binding of the transcription factor Sp1 also potentially contributes to allelic expression differences in females. Our results show that monoallelic expression of human ATP10A is variable in the population and is influenced by both gender and common genetic variation.

SUBMITTER: Hogart A

PROVIDER: S-EPMC2830741 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Gender influences monoallelic expression of ATP10A in human brain.

Hogart Amber A Patzel Katherine A KA LaSalle Janine M JM

Human genetics 20080823 3

Human chromosome 15q11-13 and the syntenic region of mouse chromosome 7 contain multiple imprinted genes necessary for proper neurodevelopment. Due to imprinting, paternal 15q11-13 deficiencies lead to Prader-Willi syndrome (PWS) while maternal 15q11-13 deficiencies cause Angelman syndrome (AS). The mechanisms involved in parental imprinting of this locus are conserved between human and mouse, yet inconsistencies exist in reports of imprinting of the maternally expressed gene Atp10a/ATP10A. Exce ...[more]

PMID: 18726118

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Project description:BackgroundMonoallelic expression (MAE) is a frequent genomic phenomenon in normal tissues, however its role in cancer is yet to be fully understood. MAE is defined as the expression of a gene that is restricted to one allele in the presence of a diploid heterozygous genome. Constitutive MAE occurs for imprinted genes, odorant receptors and random X inactivation. Several studies in normal tissues have showed MAE in approximately 5-20% of the cases. However, little information exists on the MAE rate in cancer. In this study we assessed the presence and rate of MAE in melanoma. The genetic basis of melanoma has been studied in depth over the past decades, leading to the identification of mutations/genetic alterations responsible for melanoma development.MethodsTo examine the role of MAE in melanoma we used 15 melanoma cell lines and compared their RNA-seq data with genotyping data obtained by the parental TIL (tumor infiltrating lymphocytes). Genotyping was performed using the Illumina HumanOmni1 beadchip. The RNA-seq library preparation and sequencing was performed using the Illumina TruSeq Stranded Total RNA Human Kit and subsequently sequenced using a HiSeq 2500 according to manufacturer's guidelines. By comparing genotyping data with RNA-seq data, we identified SNPs in which DNA genotypes were heterozygous and corresponding RNA genotypes were homozygous. All homozygous DNA genotypes were removed prior to the analysis. To confirm the validity to detect MAE, we examined heterozygous DNA genotypes from X chromosome of female samples as well as for imprinted and olfactory receptor genes and confirmed MAE.ResultsMAE was detected in all 15 cell lines although to a different rate. When looking at the B-allele frequencies we found a preferential pattern of complete monoallelic expression rather then differential monoallelic expression across the 15 melanoma cell lines. As some samples showed high differences in the homozygous and heterozygous call rate, we looked at the single chromosomes and showed that MAE may be explained by underlying large copy number imbalances in some instances. Interestingly these regions included genes known to play a role in melanoma initiation and progression. Nevertheless, some chromosome regions showed MAE without CN imbalances suggesting that additional mechanisms (including epigenetic silencing) may explain MAE in melanoma.ConclusionThe biological implications of MAE are yet to be realized. Nevertheless, our findings suggest that MAE is a common phenomenon in melanoma cell lines. Further analyses are currently being undertaken to evaluate whether MAE is gene/pathway specific and to understand whether MAE can be employed by cancers to achieve a more aggressive phenotype.

Project description:Gender differences in brain development and in the prevalence of neuropsychiatric disorders such as depression have been reported. Gender differences in human brain might be related to patterns of gene expression. Microarray technology is one useful method for investigation of gene expression in brain. We investigated gene expression, cell types, and regional expression patterns of differentially expressed sex chromosome genes in brain. We profiled gene expression in male and female dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum using the Affymetrix oligonucleotide microarray platform. Differentially expressed genes between males and females on the Y chromosome (DBY, SMCY, UTY, RPS4Y, and USP9Y) and X chromosome (XIST) were confirmed using real-time PCR measurements. In situ hybridization confirmed the differential expression of gender-specific genes and neuronal expression of XIST, RPS4Y, SMCY, and UTY in three brain regions examined. The XIST gene, which silences gene expression on regions of the X chromosome, is expressed in a subset of neurons. Since a subset of neurons express gender-specific genes, neural subpopulations may exhibit a subtle sexual dimorphism at the level of differences in gene regulation and function. The distinctive pattern of neuronal expression of XIST, RPS4Y, SMCY, and UTY and other sex chromosome genes in neuronal subpopulations may possibly contribute to gender differences in prevalence noted for some neuropsychiatric disorders. Studies of the protein expression of these sex-chromosome-linked genes in brain tissue are required to address the functional consequences of the observed gene expression differences. Experimental design: Two groups of male control subjects and female control subjects were selected that had no history of psychiatric disorder. Each subject was analyzed by microarray in 3 brain regions: AnCg (anterior cingulate cortex), DLPFC (dorsalateral prefrontal cortex), and CB (cerebellum). Total RNA aliquots for some subjects were analyzed at either 1 site, 2 sites, or 3 sites (UM , University of Michigan); UCD (University of California, Davis); or UCI (University of California, Irvine). The data was analyzed by looking at each Male vs Female comparison separately at each site by a t-test for gender differences. Thus for one brain region, a Male vs Female comparison was run at 3 sites, and the overlapping significant genes from the three comparisons were reported. We appreciate the assistance of Richard Stein, Ph.D. and Preston Cartagena, Psy.D. for their contributions to postmortem clinical characterization of subjects. We acknowledge Kathleen Burke as well as Jacque Berndt and the investigators and medical examiners at the Orange County Coroners Office for procurement of brain tissue. We also appreciate the technical contributions of Kevin Overman, Sharon Burke, and Phong Nguyen. F. Warren Lovell, M.D, performed a neuropathological evaluation of the postmortem brains. Tissue specimens were processed and stored at the Human Brain and Spinal Fluid Resource Center, Veteran's Medical Center, Los Angeles under the direction of Wallace W. Tourtellotte, M.D., Ph.D. This project is supported by the NIMH Conte Center Grant P50 MH60398, Pritzker Neuropsychiatric Disorders Research Consortium, William Lion Penzner Foundation (UCI), Della Martin Foundation (UCI), NIMH Grant #MH54844 (EGJ), W.M. Keck Foundation (EGJ), and the NIMH Program Project MH42251 (SJW and HA). The authors are members of of a Conte Center supported by the NIMH and the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. A shared intellectual property agreement exists between this philanthropic fund and the University of Michigan, the University of California, and Stanford University to encourage the development of appropriate findings for research and clinical applications. Keywords: other

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Gender influences monoallelic expression of ATP10A in human brain.

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Gender influences monoallelic expression of ATP10A in human brain.

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