Altered genomic imprinting as a basis for FASD placental growth defects

描述（由申请人提供）：在怀孕期间饮酒在我们的社会中很普遍，尽管它被证明与出生缺陷和严重精神障碍的发展有关。40%的妇女报告说，她们在怀孕期间喝过一些酒，3-5%的妇女由于上瘾而大量饮酒。因此，每1000例活产中有9.1例表现出一定程度的胎儿酒精谱系障碍（FASD），相关的年度医疗保健费用约为50亿美元。从使用各种模式生物的研究中，我们现在承认染色质结构的表观遗传修饰提供了环境致畸剂和导致疾病表型的基因表达改变之间的合理联系。许多独立实验室的工作表明，乙醇有能力作为一种强大的表观遗传干扰剂，破坏指导哺乳动物发育的转录过程。虽然这些表观遗传改变不会引起基因突变，但它们仍然会改变发育过程并引起疾病。这在怀孕早期尤其如此，此时表观遗传过程建立了印迹基因的复杂转录调控。基因组印记调控基因的正确调控可能是胎盘发育和功能中最重要的调控途径之一。重要的是，胎盘异常和生长迟缓是FASD的定义表型。值得进一步注意的是，有几例报告称，婴儿出生时患有与FASD相关的生长缺陷，母亲在怀孕期间没有饮酒，但父亲是慢性酗酒者。本申请的创新性方面在于其利用表观遗传发育编程的已建立模型来同时检查FASD生物学的两个研究不足的方面的方法：1）改变的印迹基因表达在FASD胎盘生长缺陷的发生中的作用和2）男性乙醇消耗对发育编程的影响。基于表观遗传学的治疗现在构成了一线癌症治疗的重要组成部分，并在阻断癌症进展方面取得了显着进展。随着我们对控制早期发育的表观遗传机制的理解的增加，这些化合物很可能会在其他治疗应用中发现效用，包括FASD的产前治疗。然而，了解产前酒精暴露如何影响染色质组织和产前酒精暴露导致的表观遗传变化的性质仍然是胎儿酒精研究领域的主要障碍。

DESCRIPTION (provided by applicant): Alcohol consumption during pregnancy is widespread in our society despite its proven association with the development of birth defects and severe mental impairment. Forty percent of all women report the consumption of some alcohol during the course of their pregnancy and 3-5% drink heavily as a result of addiction. Consequently, 9.1 cases per 1000 live births exhibit some degree of fetal alcohol spectrum disorder (FASD) with an associated annual health care cost of approximately 5 billion dollars. From studies using a diverse range of model organisms, we now acknowledge epigenetic modifications to chromatin structure provide a plausible link between environmental teratogens and alterations in gene expression leading to disease phenotypes. Work from a number of independent laboratories has demonstrated that ethanol has the capacity to act as a powerful epigenetic disruptor and derail the transcriptional processes directing mammalian development. Although these epigenetic alterations do not induce genetic mutations, they none-the-less alter the course of development and cause disease. This is especially true during early pregnancy when epigenetic processes establish the complex transcriptional regulation of imprinted genes. The proper control of genes regulated by genomic imprinting is perhaps one of the most important regulatory pathways involved in the development and function of the placenta. Importantly, placental abnormalities and growth retardation are defining phenotypes of FASDs. Of further note, several instances have been reported where infants were born with characteristic FASD associated growth defects to mothers who had not consumed alcohol during pregnancy; but whose fathers were chronic alcoholics. The innovative aspect of this application lies in its approach to utilize an established model of epigenetic developmental programming to simultaneously examine two poorly studied aspects of FASD biology: 1) the role of altered imprinted gene expression in the genesis of FASD placental growth defects and 2) the impact of male ethanol consumption on developmental programming. Epigenetic-based treatments now constitute a significant portion of front-line cancer therapies and have achieved remarkable progress in blocking cancer progression. As our understanding of the epigenetic mechanisms controlling early development increases, it is likely these compounds will find utility in other therapeutic applications including the prenatal treatment of FASDs. However, understanding how prenatal exposure to alcohol impacts chromatin organization and the nature of the epigenetic changes that result from prenatal ethanol exposure remain major barriers in the field of fetal alcohol research.