The major focus of the laboratory is the epigenetic regulation of transcription in mammals. Specifically, we are interested in molecular mechanisms by which transcription is regulated by chromatin structure and DNA methylation. This includes the identification of regulatory elements involved in establishing and maintaining epigenetic states of transcriptionally active and repressed genes. Our research employs two classic systems of epigenetic regulation in mammals: X chromosome inactivation and genomic imprinting. For most genes in diploid mammalian tissues, both copies of each gene are regulated and transcribed identically. However, X-linked genes subject to X chromosome inactivation in females and autosomal genes subject to genomic imprinting transcribe only one of the two gene copies. Our laboratory studies the molecular mechanisms responsible for establishing and maintaining these two systems of monoallelic gene expression. We currently are focusing on identifying and characterizing regulatory elements involved in activating and repressing transcription by these two epigenetic processes. For X chromosome inactivation, we study regulation of the X-linked Hprt (hypoxanthine phosphoribosyltransferase) gene, and for genomic imprinting we study regulation of the SNRPN/Snrpn and MKRN3/Mkrn3 genes on human chromosome 15 and mouse chromosome 7. We are particularly interested in the roles DNA methylation and chromatin structure play to regulate differential transcription of the active and inactive alleles of these genes. For X chromosome inactivation, we are using functional genetic approaches to study cis-acting elements that mediate the establishment and/or maintenance of chromatin structure and DNA methylation patterns in the Hprt locus on the active and inactive X chromosomes. For genomic imprinting, we are examining mechanisms involved in the parent-of-origin regulation of genes in the Angelman/Prader-Willi syndrome (AS/PWS) region on human chromosome 15 and mouse chromosome 7. We are particularly interested in mechanisms by which the AS/PWS imprinting center regulates parent-of-origin expression of genes throughout this region.