Transcriptional Silencing of the X-chromosome

描述（由申请人提供）：表观遗传调控基因表达的改变是肿瘤发生的关键决定因素，但涉及表观遗传编程和印迹的分子细节尚不清楚。X染色体失活（XCI）是一种表观遗传事件，在雌性细胞中，当基因剂量相等时，印迹会触发X染色体的转录沉默。在早期女性胚胎中调控XCI的分子细节尚不清楚，X在着床前胚胎中的转录状态近年来成为该领域一个有争议的话题。新的证据表明，父系X （XP）在胚胎早期是转录沉默的，这表明胚胎可能遗传了一个转录沉默的XP，沉默起源于精子发生过程。这项研究计划将确定是否存在连续的XP转录沉默（从精子发生到受精卵）。在减数分裂后的精子和着床前胚胎的不同发育阶段，将确定X的转录状态和各种X连锁基因的表达水平。本研究将为进一步研究表观遗传调控的染色体沉默机制奠定基础。

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.