Cellular differentiation from pluripotency is dependent on global shifts in genomic expression patterns and preservation of inherited transcriptional states throughout development of the mouse embryo. 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. X-chromosome inactivation (XCI) in the preimplantation mouse embryo is a model for epigenetic studies. The epiblast precursor cells, unlike the primitive endoderm or trophectoderm, undergo imprinted XCI, then reactivation, and finally random XCI during implantation. This cycle of inactivation, termed reprogramming, was hypothesized to occur because of loss of Xist non-coding RNA coating. However, it is now known that Xist expression is not required for initiation of imprinted XCI in the preimplantation mouse embryo, thereby leaving open the question as to whether epiblast precursor cells actually ever undergo imprinted XCI. Experiments are proposed to answer this question as well as determine if reactivation of the paternal-X is observed - does it occur via a Xist-dependent mechanism. Although certain genetic requirements for XCI have been identified, much remains unknown about how a single X chromosome is targeted and then maintained in a silenced state. A large-scale analysis of gene silencing and chromatin structure over the X chromosome using trophoblast stem (TS) cell lines that exhibit imprinted XCI will be undertaken. This global analysis will molecularly define XCI at an unprecedented level. A high-throughput method to identify genomic regions of the inactive X-chromosome that physically interact is also being developed, allowing correlation of gene activity and local chromatin modifications with 3-dimensional chromosome structure.
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 remodeling proteins and non-coding RNAs have demonstrated their ability to disrupt histone-DNA contacts and reposition nucleosomes. Consequently, these complexes are critical in regulating global gene expression. Genetic experiments that elucidate the biological specificity of these proteins and non- coding RNAs, along with the abnormal outcomes associated with disease states when inappropriately expressed, ultimately may lead to targeted epigenetic disease treatments.
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