Epigenetic Mechanisms of X-chromosome Inactivation

细胞通过继承其前身的基因表达谱来保持其特性。在细胞分裂中存活下来的转录模式被认为部分是通过组蛋白和DNA的共价修饰建立和维持的，而不涉及DNA序列本身的变化。越来越多的新证据表明，这种表观遗传模式在无数的发育过程中，也是人类疾病的原因或重要贡献者。我的研究致力于通过对x染色体失活（XCI）的研究来进一步了解表观遗传机制。XCI是哺乳动物中剂量补偿的一种工具，可导致早期雌性胚胎中两条x染色体中一条基因的转录沉默。一旦在单个细胞中发挥作用，XCI就会稳定地传播，从而使所有后代细胞保持该x染色体的沉默。由于整个染色体失活，因此很容易被检测到，XCI是研究转录记忆机制的模型系统。重要的是，在XCI期间运行的记忆机制也广泛适用于基因调控，并且被发现在XCI期间的细胞命运决定中很重要

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.