Transcriptional Silencing of the X-chromosome

描述（由申请人提供）：表观遗传学调节的基因表达的改变是肿瘤发生的关键决定因素，但表观遗传编程和印记中涉及的分子细节尚未得到很好的理解。X染色体失活（XCI）是一种表观遗传事件，其中印记在雌性细胞中触发相同基因剂量的X转录沉默。在早期女性胚胎中调控XCI的分子细节尚不清楚，X在植入前胚胎中的转录状态最近成为该领域有争议的话题。新的证据表明，父方X（XP）在早期胚胎中是转录沉默的，这表明胚胎可能遗传了转录沉默的XP，其沉默起源于精子发生过程。这项研究计划将确定是否存在XP转录沉默的连续体（从精子发生到受精卵）。X的转录状态和各种X连锁基因的表达水平将在减数分裂后的精子细胞和植入前胚胎的不同发育阶段中确定。这项研究将为未来研究表观遗传调控的染色体沉默机制提供基础。

DESCRIPTION (provided by applicant): Alterations in epigenetically-regulated gene expression are critical determinants for oncogenesis, yet the molecular details involved in epigenetic programming and imprinting are not well understood. X-chromosome inactivation (XCI) is an epigenetic event where imprinting triggers transcriptional silencing of the X for equal gene dosage in female cells. The molecular details regulating XCI in the early female embryo are not well understood, and the transcriptional status of X in the preimplantation embryo has recently become a controversial topic in the field. New evidence indicates that the paternal X (XP) is transcriptionally silent in the early embryo, suggesting that the embryo may have inherited a transcriptionally silent XP with silence originating during spermatogenesis. This research proposal will determine whether a continuum of XP transcriptional silence (from spermatogenesis into the fertilized zygote) exists. The transcriptional status of X and expression levels of various X-linked genes will be determined in post-meiotic spermatids and at different developmental stages in the pre-implantation embryo. This research will provide a foundation for future investigations into epigenetically-regulated chromosomal silencing mechanisms.