Molecular mechanisms of dosage compensation in Drosophila

剂量补偿是具有异型性染色体的物种的一个调节过程，它确保X染色体基因在单个雄性X染色体和两个雌性X染色体上的表达程度相同。对于雄性果蝇来说，不能将驻留在雄性X染色体上的基因的表达增加两倍是致命的。剂量补偿是一种涉及雄性X染色体结构修饰的表观遗传过程，涉及剂量补偿复合物（DCC）与染色质的关联。DCC是由多种酶和非编码RNA组成的染色质重塑机制。剂量补偿涉及MOF对组蛋白H4的乙酰化，MOF是一种与dcc相关的组蛋白乙酰转移酶。组蛋白修饰导致x连锁基因转录增加，这一过程尚不清楚，但可能涉及高阶染色质折叠的松动。剂量补偿现象提出了一些重要的问题，主要围绕(1)染色质重塑因子靶向限制性染色体结构域，(2)非编码RNA在表观遗传调控现象中的作用，以及(3)组蛋白修饰在高阶结构水平上影响染色质结构和功能的机制。我们的目标是通过在体外重组DCC和剂量补偿染色质，并通过建立一个体内系统来解剖DCC结构和功能的分子决定因素，来回答这些问题。

Dosage compensation is a regulatory process of species with heteromorphic sex chromosomes that assures that X chromosomal genes are expressed to an equivalent extent from the single male X chromosome and two female X-chromosomes. Failure to increase the expression of genes residing on the male X chromosome by two fold is lethal for male Drosophila. Dosis compensation is an epigenetic process involving the modification of male X chromosome structure involving the association of the dosage compensation complex (DCC) with chromatin. DCC is a chromatin remodeling machinery composed of several enzymes as well as non-coding RNA. Dosis compensation involves the acetylation of histone H4 by MOF, a DCC-associated histone acetyl transferase. The histone modification leads to an increased transcription of X-linked genes in a process that is poorly understood, but likely to involve a loosening of higher order chromatin folding. The phenomenon of dosis compensation poses a number of important questions centering around (1) the targeting of chromatin remodeling factors to a restricted chromosomal domain, (2) the role of non-coding RNA in epigenetic regulatory phenomena and (3) the mechanisms by which histone modifications affect the structure and function of chromatin at the higher order structural level. Our aim is to answer these questions by reconstituting DCC and dosis-compensated chromatin from recombinant components in vitro, and by establishing an in vivo system for the dissection of the molecular determinants of DCC structure and function.