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We study unusual gene regulatory mechanisms involved in the specification of individual cell type in the nervous and immune systems. Taking genome-scale approaches, we are exploring the role of epigenetics in understanding heritability of complex human diseases.
A major focus is on a class of autosomal genes with properties similar to X-inactivation: random monoallelic expression and asynchronous replication. Our work has shown that there are more genes on autosomes with these unusual properties than the number of genes on the X-chromosome. Using molecular biology, microarray technology and informatics we are dissecting underlying mechanisms of monoallelic expression and chromosome-pair non-equivalence.
Our work on non-coding RNAs has recently shown that NEAT1 RNA has a structural role in the nucleus.
Another focus is on alternative splicing. The Drosophila Dscam (Down syndrome cell adhesion molecule) gene is essential for axon guidance and has over 38,000 possible alternative splice forms. Using a custom made microarray we found that each cell type expresses a broad, yet distinctive spectrum of Dscam isoforms. Single cell RT-PCR experiments then showed that individual cells express ~15-50 distinct mRNAs. Thus, each individual cell’s Dscam repertoire is different from those of its neighbors, providing a potential mechanism for the generation of unique cell identity in the nervous system and elsewhere. We are also investigating mammalian genes whose alterative splicing might be used to similarly generate diversity.
Recently, we have begun to exploit the power of Affymetrix SNP genotyping arrays and next-generation sequencing, making modifications facilitating the exploration of DNA methylation differences and other epigenetic differences between alleles. These approaches allow us to explore epigenetic polymorphism across the entire genome, and to investigate the role of epigenetics in complex genetic disease.
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