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的过程中起作用，如基因表达。X染色体失活是一种实验上可验证的现象，在这种现象中，特定DNA序列位置的调节变化与基因表达的控制有关。在哺乳动物雌性细胞中，一条X染色体沉默以补偿雄性和雌性之间X连锁基因的剂量，这一过程对雌性的生存至关重要。在这里，我们建议研究伴随X染色体失活的X染色体核组织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情况下的基因表达。

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.