X-chromosome inactivation (XCI) is a paradigm of epigenetic gene regulation. XCI results in transcriptional silencing of genes along one of the two X-chromosomes in female mammals and leads to equivalence of X-linked gene dosage with that of XY males. Once enacted in individual cells of the early female embryo, XCI is stably transmitted such that all descendant cells maintain silencing of that X chromosome. Since an entire chromosome is inactivated and therefore easily detected, XCI is a model system to gain insights into the machinery that maintains transcriptional memory. Importantly, the memory mechanisms that operate during XCI often apply to gene silencing elsewhere and are being found to go awry in human disorders. ? ? Proteins encoded by the Polycomb group (PcG) mediate long-term repression of genes, including during XCI. PcGs are found enriched on the Xi early during XCI, leading to the idea that they help initiate XCI. In this application, the candidate will test if PcGs are required to initiate imprinted XCI during early embryogenesis. He has recently detected the enrichment of a novel protein on the Xi by immunofluorescence; here he proposes to identify the protein, characterize its biochemical function in epignenetic inheritance, and define its requirement during XCI. ? ? The award will considerably facilitate the candidate's goal of establishing an independent laboratory with the focus of genetically and biochemically defining factors and their function in epigenetic gene regulation. The mentor's laboratory provides a stimulating environment for conducting epigenetic research in the mammalian system. During the mentored phase of the award, the candidate will determine if PcGs initiate imprinted XCI and also identify as well as characterize a novel protein that is enriched on the Xi. This will involve refining techniques in defining XCI defects in pre-implantation stage embryos and in protein identification. In the independent phase of the award, the candidate will delineate a function to the novel Xi-enriched protein and identify interacting components. In this phase, he will also define the requirement of the novel gene in specific phases of XCI. ? ? Emerging evidence increasingly implicates the misregulation of the epigenetic machinery as a cause of or a significant contributor to human disease. The identification and delineation of novel epigenetic factors and their function will provide insight into the mechanisms that are either bypassed or co-opted in human disorders, including various cancers. ? ? ?
| Maclary, Emily; Buttigieg, Emily; Hinten, Michael et al. (2014) Differentiation-dependent requirement of Tsix long non-coding RNA in imprinted X-chromosome inactivation. Nat Commun 5:4209 |
| Kalantry, Sundeep; Purushothaman, Sonya; Bowen, Randall Bryant et al. (2009) Evidence of Xist RNA-independent initiation of mouse imprinted X-chromosome inactivation. Nature 460:647-51 |
