Epigenetics is defined by the organization of the eukaryotic genome within chromatin and the involvement of this organization in the regulation of DNA metabolism (transcription, replication, repair and recombination). This definition has been evolving to encompass the many processes that cannot be accounted for by simple changes in DNA sequence. Abnormalities of epigenetic mechanisms result in human disorders that include developmental anomalies and cancer. The Magnuson lab focuses on the role of mammalian polycomb-group proteins in unique epigenetic phenomena such as genomic imprinting and X-chromosome inactivation. In addition, the lab works on the role of mammalian SWI/SNF complexes, which displace nucleosomes from promoter regions of target genes. Finally, to facilitate functional genomic analyses, the Magnuson lab has also developed a genome-wide mutagenesis strategy for mice. Mutagenesis has long been a fundamental tool for the genetic analysis of experimentally tractable organisms such as yeast, fruit flies, and nematodes. However, despite a long history of the mouse as a model system for mammalian genetics, as well as a decade of gene-targeting experiments, mutations exist for only a small percentage of its genes. The lab has overcome the limitations of mutagenesis in the mouse by developing methods capable of systematically generating mutations in all genes of totipotent embryonic-stem (ES) cells. A mutagenized library of 4,000 clonal ES-cell lines has been created, from which 15-25 alleles of any gene can be isolated. Mice can then be derived from the mutagenized cells carrying anyone of the alleles. Our goal is to create a comprehensive collection of variant alleles for all genes in the mouse.