Academic journal article Alcohol Research: Current Reviews

Prenatal Alcohol Exposure and Cellular Differentiation: A Role for Polycomb and Trithorax Group Proteins in FAS Phenotypes?

Academic journal article Alcohol Research: Current Reviews

Prenatal Alcohol Exposure and Cellular Differentiation: A Role for Polycomb and Trithorax Group Proteins in FAS Phenotypes?

Article excerpt

Exposure of the developing embryo and fetus to alcohol can have profound adverse effects on physical, behavioral, and cognitive development. The resulting deficits collectively have been termed fetal alcohol spectrum disorders (FASD). They range in severity from mild cognitive deficits to a well-defined syndrome (i.e., fetal alcohol syndrome [FAS]), which is broadly characterized by low birth weight, distinctive craniofacial malformations, smaller-than-normal head size (i.e., microcephaly), and central nervous system dysfunction (Riley et al. 2011). The mechanisms underlying ethanol's harmful effects on development are not yet fully understood. Studies in recent years have indicated that epigenetic mechanisms may play a role in the etiology of FASD. This article describes the proposed roles of epigenetic mechanisms in FASD and cell differentiation in general and introduces two protein complexes that are hypothesized to play central roles in these events.

Role of Epigenetics in Developmental Programming and FASD

Mammalian development consists of a series of carefully orchestrated changes in gene expression that occur as stem or progenitor cells differentiate to form the tissues and organs making up the growing fetus. (1) Once the identity of each new cell type has been established by lineage-specific transcription factors, this identity is maintained through unique alterations in the way in which the DNA encoding each gene becomes packaged around certain proteins (i.e., the histones) within the chromatin structure of the nucleus (Hemberger et al. 2009). Much like a closed book cannot be read whereas an open book can, the DNA can either be tightly wound up into a structure that silences the encoded genes, or the DNA can be in a relaxed, open, and active state. As development proceeds, the DNA of each cell becomes packaged in a way that is unique to that cell type and thus is programmed to express only a specific set of genes that confer the cell's individual identity and physiological function (Barrero et al. 2010). Three enzymatic mechanisms control the assembly and regulation of chromatin structure: DNA methylation, modification of the histone proteins (i.e., posttranslational histone modification), and ATP-dependent chromatin remodeling (Barrero et al. 2010). These fundamental modifications, which control gene packaging, are passed on to the daughter cells when a cell divides. They are referred to as epigenetic changes because they impart a level of regulation that is above ("epi") the direct genetic modifications of the DNA (Hemberger et al. 2009).

Studies using a diverse range of model organisms have led to the conclusion that epigenetic modifications to the chromatin structure provide a plausible link between exposure to environmental substances that can harm the developing fetus (i.e., teratogens) and lasting alterations in gene expression leading to disease phenotypes. Numerous studies have demonstrated that exposure to ethanol is associated with both genome-wide and gene-specific changes in DNA methylation (Bielawski et al. 2002; Downing et al. 2011; Garro et al. 1991; Haycock and Ramsey 2009; Hicks et al. 2010; Liu et al. 2009; Ouko et al. 2009; Zhou et al. 2011), alterations in posttranslational histone modifications (Kim and Shukla 2005; Pal-Bhadra et al. 2007; Park et al. 2005), and a profound shift in epigenetically sensitive phenotypes (Kaminen-Ahola et al. 2010). Collectively, all of these observations indicate that ethanol can act as a powerful epigenetic disruptor and alter chromatin structure.

Although the mechanisms by which alcohol impacts chromatin structure are not completely understood, recent work suggests that some epigenetic changes result from altered cellular metabolism. For example, Choudhury and colleagues (2010) observed an increase in reactive oxygen species (ROS) within primary rat liver cells (i.e., hepatocytes) treated with ethanol. This increase in ROS was correlated with an increase in a specific modification of histone 3 (i. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.