Stochastic and imprinted monoallelically expressed genes influence cellular differentiation and development. Imprinted genes are expressed in a parent-of-origin manner, whereas in stochastic monoallelic expression either the maternal or paternal allele is active in a cell. Classically, imprinting is known to play a key role in the development of the neuropsychiatric disorders Prader-Willi Syndrome and Angelman Syndrome. In addition, parent-of-origin effects have also been found in a subset of families with schizophrenia (SZ), autism spectrum disorders (ASD) and bipolar disorder (BD). Both stochastic monoallelic expression and imprinting of brain-expressed genes could help explain some interesting epidemiological features of neuropsychiatric disorders, such as discordance in monozygotic twins and reduced penetrance. Two experimental tools have emerged that provide the means to evaluate the role of monoallelic (also known as allele-biased) gene expression in neuronal differentiation and neuropsychiatric disorders; induced pluripotent stem cell (iPSC) technology, and whole transcriptome sequencing (RNA-Seq). To identify monoallelically expressed genes, we carried out a preliminary RNA-Seq analysis of neurons derived from a control iPSC line and genotyped DNA using the Affymetrix Genome-Wide Human SNP Array 6.0. Heterozygous SNPs were identified and RNA-Seq reads across them were analyzed. We found evidence for allele-biased expression in 801 genes. In addition, a statistically significant enrichment for SZ and ASD candidate genes was found, which included A2BP1 (RBFOX1), ERBB4, NLGN4X, NRG1, NRG3, NRXN1, and NLGN1. A2BP1 is particularly interesting because as a regulator of neuronal gene splicing disrupting its expression has the capacity to influence numerous downstream targets. In this current proposal, we will explore the mechanism of allele-biased expression and determine whether the phenomenon is caused by cis-acting genetic factors, or by an epigenetic process leading to either imprinting or stochastic monoallelic expression. The epigenetic basis underlying allele-biased expression in differentiating human neurons will be explored by carrying out genome-wide DNA methylation and chromatin immunoprecipitation studies. Upon completion of these studies we will be able to group a large number of SZ, ASD and BD candidate genes into a common functional umbrella: regulation by allele-biased expression, a finding that will provide the foundation for epigenetic-based treatment strategies.
Using a new method for studying disease called induced pluripotent stem (iPS) cell technology we are now able to grow human neurons (nerve cells) in the laboratory. iPS cells are usually derived from skin and blood cells. They are capable of being turned into any other cell type, including neurons and other cell types found in the brain, such as astrocytes and oligodendrocytes. By making iPS cells from patients with schizophrenia, autism and other neuropsychiatric disorders, we can grow patient-specific neurons with relative ease. These neurons can be used to study the underlying molecular and genetic basis of these disorders and for testing new drugs.
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