Investigation of X chromosome organization before the onset of X-inactivation

描述（由申请人提供）：细胞核内亚结构和DNA序列的位置是高度组织化的，这种组织在调节染色质依赖性过程（如基因表达）中起作用。X染色体失活是一种实验上可行的现象，其中特定DNA序列位置的调节变化涉及基因表达的控制。在哺乳动物雌性细胞中，一条X染色体被沉默，以补偿雄性和雌性之间的X连锁基因的剂量，这一过程对雌性生存至关重要。在这里，我们建议调查的X染色体核组织，伴随X失活的调节变化的分子基础。所获得的见解可能更普遍适用，因为许多调节X失活的因素也调节其他环境中的基因表达。 公共卫生相关性：在哺乳动物发育的早期，每个细胞中的一条X染色体被沉默，以平衡XY雄性和XX雌性之间的X连锁基因剂量。X-失活对于哺乳动物雌性的生存是必不可少的，并且许多调节X-失活的因子也调节其他环境中的基因表达。我们建议研究X染色体失活过程中X染色体结构变化的分子基础.这将提供关于核组织在X-灭活中的作用的重要信息， 与理解核组织如何影响基因组其余部分的基因表达有关。

DESCRIPTION (provided by applicant): The position of substructures and DNA sequences within the nucleus is highly organized, and this organization plays a role in regulating chromatin-dependent processes, such as gene expression. X chromosome inactivation is an experimentally amenable example of a phenomenon in which regulated changes in the location of specific DNA sequences is implicated in control of gene expression. In mammalian female cells, one X chromosome is silenced for dosage compensation of X-linked genes between males and females, and this process is essential for female survival. Here, we propose to investigate the molecular basis of the regulated changes in X chromosome nuclear organization that accompany X-inactivation. The insights gained are likely to be more generally applicable, since many of the factors that regulate X-inactivation also regulate gene expression in other contexts. PUBLIC HEALTH RELEVANCE: Early in mammalian development, one of the X chromosomes is silenced in each cell, to equalize X- linked gene dosage between XY males and XX females. X-inactivation is essential for survival of mammalian females, and many of the factors that regulate X-inactivation also regulate gene expression in other contexts. We propose to study the molecular basis of changes in X chromosome organization during X- inactivation. This will provide important information about the role of nuclear organization in X- inactivation and will be relevant to understanding how nuclear organization impacts gene expression for the rest of the genome.