Biochemical dissection of epigenetic inheritance by Polycomb group proteins.

描述（申请人提供）：表观遗传机制通过细胞分裂维持基因调控信息，使基因表达模式稳定。由果蝇多梳群（PcG）基因编码的蛋白质在发育过程中维持基因表达的关键模式，可能是通过染色质结构的遗传改变。PcG基因及其功能在哺乳动物中是保守的，它们在癌症中也被错误调控，并与肿瘤进展有关。在细胞周期中，基于染色质的表观遗传信息面临着DNA复制和有丝分裂两个挑战。在我们最初的提案中，我们讨论了pcg依赖性基因调控如何通过DNA复制遗传。修订的目的是解决PcG效应如何通过有丝分裂遗传。在有丝分裂过程中，染色体发生了剧烈的结构和生化变化，包括许多基因调控因子的丢失。获取基于染色质的基因调控信息

DESCRIPTION (provided by applicant): Epigenetic mechanisms make gene expression patterns stable by maintaining gene regulatory information through cell divisions. Proteins encoded by the Drosophila Polycomb Group (PcG) genes maintain key patterns of gene expression during development, likely through heritable alterations to chromatin structure. PcG genes and their functions are conserved in mammals where they are also misregulated in cancer, and associated with tumour progression. During the cell cycle, chromatin-based epigenetic information faces two challenges, DNA replication and mitosis. In our original proposal, we addressed how PcG-dependent gene regulation may be inherited through DNA replication. The revision aims address how PcG effects can be inherited through mitosis. During mitosis, chromosomes undergo dramatic structural and biochemical changes, including the loss of many gene regulatory factors. For chromatin based gene regulatory information to be maintained through mitosis, regulators must either remain associated with mitotic chromatin or mark the chromatin to direct their return. To determine whether PcG proteins themselves could transmit gene regulatory information through mitosis, we will determine what fraction of PcG proteins is retained on chromosomes in mitosis. To understand how chromatin binding by PcG proteins can be maintained or disrupted during mitosis, we will ask whether specific proteins associate with PcG complexes during mitosis, and whether proteins present in extracts from mitotic cells affect the activity of PcG proteins. How PcG proteins behave during mitosis and how this behavior is regulated is important for understanding how PcG-dependent gene regulation is maintained through mitosis, and may have more general implications for epigenetic mechanisms. PUBLIC HEALTH RELEVANCE: Epigenetic mechanisms help maintain cell identities through development by making patterns of gene expression stable. Polycomb proteins are epigenetic regulators of development and are upregulated in many cancers, and are specifically correlated with aggressive cancer progression and poor outcome. This study aims to understand how these proteins function during normal cell division. This will help understand how disruption of their function can occur and how it contributes to tumour progression.