Cellular differentiation is dependent on global shifts in genomic expression patterns and preservation of inherited transcriptional states throughout development. This transcriptional memory can be translated directly through promoter DNA methylation or more indirectly through chromatin structure. These epigenetic changes are dynamic, extensively utilized mechanisms of gene and genome regulation. Mammalian gametogenesis requires numerous such epigenetic changes to accompany the transition from somatic, diploid precursors to mature, haploid gametes. This transition is important for the progression through meiosis, which itself requires the action of macromolecular complexes to manage the series of events entailing meiotic recombination between homologous chromosomes. Embryonic epigenetic states are first erased and reprogrammed during the development of primordial germ cells. Later, as germ cells differentiate, faithful execution of the meiotic program requires that their genomes undergo large-scale changes to histone and DNA modifications as well as to chromatin structure, all of which requiring the action of a large number of chromatin modifying pathways. The experiments outlined in this proposal are focused on elucidating the role of chromatin modifiers as facilitators of homeostasis and differentiation during mammalian spermatogenesis.
Many human diseases are the result of incorrect interpretation of genome sequence due to abnormalities in the structure of chromatin that packages DNA in the nucleus (epigenetics). Studies on chromatin modifying proteins have demonstrated their ability to disrupt histone-DNA contacts and reposition nucleosomes, thereby regulating global gene expression. Genetic experiments that elucidate the biological specificity of these proteins, along with the abnormal outcomes associated with disease states when inappropriately expressed, ultimately may lead to targeted disease treatments.
Showing the most recent 10 out of 30 publications
