Molecular and cellular mechanisms underlying asymmetric histone inheritance

描述（由申请人提供）：研究果蝇雄性生殖系干细胞不对称分裂过程中不对称组蛋白遗传的潜在机制项目概述：“表观遗传现象”的广义定义是指对基因表达或功能的影响，这些影响可通过细胞分裂遗传，而不改变初级DNA序列。表观遗传机制在调节干细胞身份和活性方面发挥重要作用。适当的表观遗传调控失败导致干细胞行为异常，这是许多疾病的基础，如糖尿病、肌肉萎缩症、神经退行性疾病、不育症和许多形式的癌症。然而，一个长期存在的问题是干细胞在分裂过程中是否保留了表观遗传记忆。如果是这样的话，干细胞特异性表观遗传记忆的消除会导致疾病吗？ 许多类型的干细胞经历不对称的细胞分裂，产生两个具有不同细胞命运的子细胞：自我更新的干细胞和分化的另一个子细胞。最近我们发现在果蝇雄性生殖系干细胞（GSC）的不对称分裂过程中，已经存在的组蛋白3（H3）被选择性地分离到GSC中，而新合成的H3则富集在分化的子细胞中。我们的研究提供了第一个直接的证据， 预先存在的组蛋白在体内细胞不对称分裂过程中，这可能有助于维持其独特的表观遗传记忆。我们假设一个两步模型的不对称H3分离：在S期预先存在的组蛋白和新合成的组蛋白差异纳入两套姐妹染色单体，然后，在有丝分裂的姐妹染色单体的集合，将预先存在的组蛋白分离到GSC，而另一组富含新合成的组蛋白的姐妹染色单体被分配到经历分化的子细胞。在这里，我们建议使用分子遗传学，细胞生物学和生物物理学的方法来理解这两个步骤的机制和生物学意义，这将对理解干细胞维持和分化中的表观遗传遗传产生深远的影响。

DESCRIPTION (provided by applicant): Studying mechanisms underlying asymmetric histone inheritance during asymmetric division of Drosophila male germ line stem cell Project Summary: A broad definition for "epigenetic phenomenon" refers to effects on gene expression or function that are inheritable through cell divisions without altering the primary DNA sequences. Epigenetic mechanisms play important roles in regulating stem cell identity and activity. Failure in appropriate epigenetic regulation leads to abnormalities in stem cell behavior, which underlies many diseases such as diabetes, muscular dystrophy, neurodegenerative disease, infertility, and many forms of cancer. However, a long-standing question has been whether stem cells retain their epigenetic memory during divisions. And if so, could abolishment of stem cell- specific epigenetic memory lead to diseases? Many types of stem cells undergo asymmetric cell divisions to give rise to two daughter cells with distinct cell fates: a self-renewed stem cel and to another daughter cell that differentiates. Recently we found that during the asymmetric division of Drosophila male germ line stem cell (GSC), the preexisting histone 3 (H3) are selectively segregated to the GSC whereas newly synthesized H3 are enriched in the differentiating daughter cell. Our studies provide the first direct evidence that stem cells retain preexisting histones during asymmetric cell divisions in vivo, which may contribute to maintain their unique epigenetic memory. We hypothesize a two-step model for asymmetric H3 segregation: during S phase preexisting histones and newly synthesized histones are differentially incorporated to two sets of sister chromatids; then, during mitosis the set of siste chromatids incorporating preexisting histones are segregated to GSCs, while the other set of sister chromatids enriched with newly synthesized histones are partitioned to the daughter cell which undergoes differentiation. Here we propose to use molecular genetics, cell biology and biophysical approaches to understand mechanisms and biological significance underlying both steps, which will have far-reaching impact on understanding epigenetic inheritance in stem cell maintenance and differentiation.