HUMAN CHROMATIN ROADMAP AND FUNCTIONAL PLASTICITY

染色体是我们所有细胞中携带基因的结构。每个人类细胞都有46条染色体。在真核细胞的细胞核中，DNA高度折叠并与特定蛋白质一起压缩成称为染色质的动态聚合物。基因表达、染色体分裂、DNA复制和修复都不是单独作用于DNA，而是作用于染色质模板。酶可以将染色质重组成可访问和不可访问的配置，这一发现揭示了大大扩展遗传密码信息潜力的机制。此外，现在已经确定染色质结构特征可以影响基因表达。体外研究支持染色质作为进入DNA的屏障的模型。因此，这种组织必须受到严格的调控和动态，以允许蛋白质-DNA相互作用对核功能至关重要。重要的是，除了遗传信息之外，基因组组织还提供了另一层信息，即所谓的表观遗传，其定义意味着它在整个细胞分裂中稳定遗传，但它不是遗传编码的。因此，每种细胞类型都将显示特定的表观基因组。我们最近构建了小型人类微型染色体，这比更大的正常染色体更容易研究。本项目提出使用我们的微型染色体作为工作模型来定义整个人类染色体的表观遗传特征。其结果将是我们对表观遗传调控、特化染色质结构域的组织和染色体行为的基础过程的知识的重大收获。

Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably extend the information potential of the genetic code. In addition, it is now established that chromatin structural features can influence gene expression. In vitro studies support a model in which chromatin functions as a barrier for the access to DNA. Therefore this organization has to be tighly regulated and dynamic to allow the protein-DNA interactions critical for nuclear functions. Importantly genome organisation provides in addition to genetic information another layer of information, so called epigenetic, which by definition means that it is stably inherited throughout cellular divisions, yet it is not encoded genetically. Thus each cell type will display a specific epigenome. We have recently constructed small human minichromosomes, which are much easier to study than the much larger normal chromosomes. The present project proposes to define the epigenetic feature across an entire human chromosome using our minichhromosomes as working models. The outcome will be a significant gain in our knowledge on the processes underlying epigenetic regulation, the organisation of specialised chromatin domain, and behaviour of the chromosomes.