Epigenetic Mechanisms of X-chromosome Inactivation

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Cells retain tlieir identity in part by inheriting gene expression profiles of their predecessors. Patterns of transcription that survive cell division are thought to be established and maintained partly through covalent modifications of histones and DNA, and do not involve changes in the DNA sequence itself. Emerging evidence increasingly implicates this epigenetic mode of inheritance in a myriad of developmental processes as well as a cause of or a significant contributor to human disease. My research strives to further our understanding of epigenetic mechanisms through the study of X-chromosome Inactivation (XCI). XCI is an instrument of dosage compensation in mammals that results in the transraiptlonal silencing of genes on one of the two X-chromosomes in eariy female embryos. Once enacted in individual cells, XCI is stably transmitted such that all descendant ceils maintain silencing of that X-chromosome. Since an entire chromosome is inactivated and tfierefore easily detected, XCI is a model system to investigate transcriptional memory mechanisms. Importantly, the memory mechanisms that operate during XCI also apply broadly to gene regulation and are being found to be important in cell fate decisions during embryogenesis and in stem cell biology as well as during disease progression. We have recently identified a novel protein enriched on the inactive X-chromosome (Xi), This protein is predicted to be a novel putative methyltransferase. The Xi is a target of two known MTases (Ezh2 and Pr- Set7), which operate on the Xi to propagate transcriptional memory by catalyzing the methylation of histones either on their own or In a complex with other proteins. We will therefore deteimine if the novel protein mediates cellular memory through histone methylation, using established biochemical assays to detect histone methylation on core histones as well as on nudeosome substrates. We also aim to Identify proteins that with which It interacts. We will also generate mice bearing a conditional-null mutation in the gene to analyze its requirement in XCI.