Veazey Kylee J, Muller Daria, Golding Michael C
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
Alcohol Res. 2013;35(1):77-85.
Exposure to alcohol significantly alters the developmental trajectory of progenitor cells and fundamentally compromises tissue formation (i.e., histogenesis). Emerging research suggests that ethanol can impair mammalian development by interfering with the execution of molecular programs governing differentiation. For example, ethanol exposure disrupts cellular migration, changes cell-cell interactions, and alters growth factor signaling pathways. Additionally, ethanol can alter epigenetic mechanisms controlling gene expression. Normally, lineage-specific regulatory factors (i.e., transcription factors) establish the transcriptional networks of each new cell type; the cell's identity then is maintained through epigenetic alterations in the way in which the DNA encoding each gene becomes packaged within the chromatin. Ethanol exposure can induce epigenetic changes that do not induce genetic mutations but nonetheless alter the course of fetal development and result in a large array of patterning defects. Two crucial enzyme complexes--the Polycomb and Trithorax proteins--are central to the epigenetic programs controlling the intricate balance between self-renewal and the execution of cellular differentiation, with diametrically opposed functions. Prenatal ethanol exposure may disrupt the functions of these two enzyme complexes, altering a crucial aspect of mammalian differentiation. Characterizing the involvement of Polycomb and Trithorax group complexes in the etiology of fetal alcohol spectrum disorders will undoubtedly enhance understanding of the role that epigenetic programming plays in this complex disorder.
接触酒精会显著改变祖细胞的发育轨迹，并从根本上损害组织形成（即组织发生）。新出现的研究表明，乙醇可通过干扰控制分化的分子程序的执行来损害哺乳动物的发育。例如，接触乙醇会破坏细胞迁移、改变细胞间相互作用并改变生长因子信号通路。此外，乙醇可改变控制基因表达的表观遗传机制。正常情况下，谱系特异性调节因子（即转录因子）建立每种新细胞类型的转录网络；然后，细胞的身份通过DNA编码每个基因在染色质中的包装方式的表观遗传改变得以维持。接触乙醇可诱导表观遗传变化，这些变化不会诱导基因突变，但仍会改变胎儿发育进程并导致大量的模式缺陷。两种关键的酶复合物——多梳蛋白和三胸蛋白——对于控制自我更新与细胞分化执行之间复杂平衡的表观遗传程序至关重要，且功能截然相反。产前接触乙醇可能会破坏这两种酶复合物的功能，改变哺乳动物分化的一个关键方面。明确多梳蛋白和三胸蛋白家族复合物在胎儿酒精谱系障碍病因中的作用，无疑将增进我们对表观遗传编程在这种复杂疾病中所起作用的理解。
