Mechanisms of epigenetic conversions in S.cerevisiae

真核生物基因组被包装在一种称为染色质的高阶复合体中。染色质除了具有明显的结构作用外，还在基因表达调控中发挥着重要作用。根据其缩合程度的不同，染色质可以允许或阻止转录因子访问其目标基因。重要的是，这种限制性或允许性的染色质结构可以通过多代细胞遗传。因此，可遗传的染色质结构确保了基因表达程序在后代中的连续性。这些染色质交易是表观遗传学专业领域的焦点。*染色质的遗传性不是永久性的。在多细胞生物体的发育过程中，染色质的允许状态和限制状态(分别称为常染色质和异染色质)之间会发生多次转换。这些开关有助于细胞分化和特化，并配置特定组织的所谓表观遗传格局。在单细胞真核生物中，这样的开关有助于适应环境。毁灭性的血液寄生虫，如锥虫和疟原虫，使用表观遗传开关来逃避免疫系统。在许多健康障碍中，特别是在癌症中，不合时宜的表观遗传开关导致了疾病的发展。尽管表观遗传转化具有明显的意义，但人们对表观遗传转化及其分子机制知之甚少。我的研究计划的目标是在这一未知的表观遗传学领域取得重大进展。*在某些基因组位置，基因偶尔会在活跃或抑制状态之间切换。这种令人着迷的基因行为(称为位置效应多样性)为研究染色质的转化提供了一个很好的模型系统。其中一种现象，即面包酵母中的端粒位置效应(TPE)，在我们理解染色质结构如何调控基因方面起到了关键作用。热塑性弹性体在许多染色质修饰因子的鉴定和表征中也起到了重要作用。在本申请中，我描述了一个程序，该程序在酿酒酵母中使用TPE来研究真核生物表观遗传转化的一般机制。我已经确定了参与这一过程的三个基因，并在理解其中一个基因CAC1的作用方面取得了一些进展。它编码一个关键的染色质组装因子CAF-I的亚基。我的短期目标是通过生物化学和遗传学实验相结合的方式继续对CAC1的研究。我建议的另一个关键方向是找到一个共同的机制，该机制由CAC1和另一个被确定为表观遗传开关调节基因(RRM3)的基因共享。这一研究计划的成果将有助于基础学术知识，但也将对健康科学和癌症领域的研究人员产生强烈的吸引力。

Eukaryotic genomes are packaged in a high-order complex called chromatin. Besides its obvious structural role, chromatin also plays a critical role in the regulation of gene expression. Depending on its level of condensation, chromatin can allow or prevent the access of transcription factors to their target genes. Importantly, such restrictive or permissive chromatin structures are heritable through multiple cell generations. Hence, heritable chromatin structures ensure the continuity of gene expression programs in the progeny. These chromatin transactions are the focus of the specialised field of epigenetics.***Heritability of chromatin is not permanent. During the development of multicellular organisms numerous switches between the permissive and restrictive states of chromatin (called euchromatin and heterochromatin, respectively) take place. These switches contribute to cell differentiation and specialization and configure the so called epigenetic landscape of the specific tissue. In single cell eukaryotes such switches help to adapt to the environment. Devastating blood parasites such as Trypanosomes and Plasmodium use epigenetic switches to evade the immune system. In many health disorders, and notably in cancer, untimely epigenetic switches contribute to the development of the disease. Despite their apparent significance, epigenetic conversions and the molecular mechanisms that govern them are poorly understood. My research program is aiming to gain significant advances in this uncharted field of epigenetics.***At certain genome positions the genes occasionally switch between the active or repressed states. This fascinating gene behaviour (known as Position-Effect-Variegation) has provided an excellent model system to study the conversions of chromatin. One such phenomenon, the so called Telomere-Position-Effect (TPE) in the baker yeast S.cerevisiae, has been pivotal in our understanding of how genes are regulated by chromatin structure. TPE has also been instrumental in the identification and characterisation of numerous chromatin modifying factors. In this application I describe a program, which is using TPE in S.cerevisiae to study the general mechanisms of epigenetic conversions in eukaryotes. I have already identified three genes that are involved in this process and have made some progress towards the understanding of the role of one of them, CAC1. It encodes subunits of a key Chromatin Assembly Factor, CAF-I. My short-term goals are to continue the studies on CAC1 by a combination of biochemical and genetic experiments. Another key direction in my proposal is to find a common mechanism shared by CAC1 and another gene that was identified as a regulator of epigenetic switches (RRM3). The outcome of this research program will contribute to fundamental academic knowledge, but will also strongly appeal to researchers in the field of health sciences and cancer.*********