Genetic Silencing in Germline Maintenance and Function

描述（申请人提供）：成年种系具有许多不同的功能，包括增殖、减数分裂突触和重组、母体和父本mRNA和蛋白质合成以及配子发生。它还具有多重义务，包括防止移动的遗传元件（转座子）造成可遗传的遗传损伤，防止生殖细胞分化成体细胞，以及建立可遗传的转录活性状态。在某种程度上，所有这些义务都是通过压制机制来履行的，这些机制采取行动，压制或防止违反这些义务的不适当活动。生殖细胞阻遏利用转录后阻遏（例如，基于RNAi的）和转录的（例如，基于染色质的）机制来实现其目标。这些机制的一个主要目标是X染色体，这是转录抑制减数分裂期间在两个性别在C。在蠕虫和哺乳动物的雄性减数分裂过程中完全失活。性染色体失活是由一个高度保守的过程介导的，该过程在减数分裂期间靶向未突触的染色质，并且可能是一种古老的基因组防御机制。我们了解了该机制的一些组成部分，并计划使用C. elegans作为一个模型系统。在哺乳动物和蠕虫中，雄性X染色体在胚胎中被“印记”优先失活，这可能是其减数分裂沉默的结果。印记X失活是遗传印记的一个引人注目的例子，但对印记的建立知之甚少。我们还将使用C. elegans来剖析雄性X印记的机制。我们已经使用了广泛的工具，可用于这种生物体，以建立一个很好的模型生物体研究生殖系抑制，或沉默，现在准备解剖染色质的作用，在生殖细胞沉默，印记建立和基因组防御机制，在这个遗传模型系统。在生殖系中运作的表观遗传机制对于建立印记和防止可遗传的基因突变至关重要，这两者对于正常的人类健康和正常的人类发育都至关重要。

DESCRIPTION (provided by applicant): The adult germ line has many disparate functions, including proliferation, meiotic synapsis and recombination, maternal and paternal mRNA and protein synthesis, and gametogenesis. It also has multiple obligations, including preventing mobile genetic elements (transposons) from inflicting heritable genetic damage, preventing differentiation of the germ cells into somatic cells, and establishing heritable states of transcriptional activity. All of these obligations are met, to some extent, by repressive mechanisms that act to silence or prevent inappropriate activities that are counter to these obligations. Germ cell repression utilizes a combination of post-transcriptional repression (e.g., RNAi-based) and transcriptional (e.g., chromatin based) mechanisms to achieve its goals. A major target of these mechanisms is the X chromosome, which is transcriptionally repressed during meiosis in both sexes in C. elegans, but is fully inactivated during male meiosis in both worms and mammals. Sex chromosome inactivation is mediated by a highly conserved process that targets unsynapsed chromatin during meiosis, and is likely an ancient genome defense mechanism. We understand some of the components of the mechanism, and plan to further dissect the mechanism and its regulation using C. elegans as a model system. In both mammals and worms, the male X is "imprinted" for preferentially inactivation in embryos, and this is likely a consequence of its meiotic silencing. Imprinted X inactivation is a dramatic example of genetic imprinting, and little is understood about imprint establishment. We will also use the genetic, molecular, biochemical, and cytological tools available in C. elegans to dissect the mechanism of male X imprinting. We have used the extensive tools available for this organism to build it into an excellent model organism for studying germ line repression, or silencing, and are now poised to dissect the role of chromatin in germ cell silencing, imprint establishment and genome defense mechanisms in this genetic model system. Epigenetic mechanisms operating in the germ line are essential for the establishment of imprinting and the prevention of heritable genetic mutations, both of which are crucial for normal human health and normal human development.