Molecular and cellular mechanisms underlying asymmetric histone inheritance

项目概述：“表观遗传现象”的广义定义是指在不改变原代DNA序列的情况下，通过细胞分裂可遗传的对基因表达或功能的影响。表观遗传机制在调节干细胞的身份和活性中起着重要作用。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、不孕症和许多形式的癌症。然而，一个长期存在的问题是干细胞是否在分裂过程中保留其表观遗传记忆。如果是这样的话，消除干细胞特异性表观遗传记忆会导致疾病吗？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：一个自我更新的干细胞和另一个分化的子细胞。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，先前存在的组蛋白3 （H3）被选择性地分离到GSC中，而新合成的H3则在分化的子细胞中富集。我们的研究提供了干细胞保留的第一个直接证据

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.