Transgenerational Epigenetics and Brain Disorders

Nadia Rachdaoui; Dipak K. Sarkar1    Rutgers Endocrine Research Program, Department of Animal Sciences, Rutgers University, New Brunswick, New Jersey, USA
1 Corresponding author: email address: sarkar@aesop.rutgers.edu

Abstract

Neurobehavioral and psychiatric disorders are complex diseases with a strong heritable component; however, to date, genome-wide association studies failed to identify the genetic loci involved in the etiology of these brain disorders. Recently, transgenerational epigenetic inheritance has emerged as an important factor playing a pivotal role in the inheritance of brain disorders. This field of research provides evidence that environmentally induced epigenetic changes in the germline during embryonic development can be transmitted for multiple generations and may contribute to the etiology of brain disease heritability. In this review, we discuss some of the most recent findings on transgenerational epigenetic inheritance. We particularly discuss the findings on the epigenetic mechanisms involved in the heritability of alcohol-induced neurobehavioral disorders such as fetal alcohol spectrum disorders.

Keywords

Neuronal disease

DNA methylation

Histone

Inheritance

Germline

Transgenerational

1 Introduction to Transgenerational Epigenetic Inheritance

Most complex human diseases such as cancer and psychiatric disorders are governed by a genetic heritable component; however, to date, genome-wide association studies failed to identify the causal loci and genetic basis of most complex diseases (Gibson, 2011). This “missing heritability” suggests that, in addition to genetically inherited information through particular loci, additional layers of information referred to as epigenetics play an important role in the inheritance of complex diseases (Bohacek & Mansuy, 2013; Danchin et al., 2011). Acquired epigenetic marks are thought to be completely erased between generations; however, several studies have shown that this epigenetic information can be transmitted through the germline. This phenomenon is known as “transgenerational epigenetic inheritance” (Daxinger & Whitelaw, 2010; Horsthemke, 2007).

Moreover, the discovery of parental imprinting also called “genomic imprinting” in the 1980s provided the first evidence that epigenetic processes persist between generations and might underlie the transgenerational epigenetic inheritance of traits and diseases (Kearns, Preis, McDonald, Morris, & Whitelaw, 2000; Reik, Collick, Norris, Barton, & Surani, 1987; Swain, Stewart, & Leder, 1987; Tost, 2009). Genomic imprinting is a non-Mendelian form of gene regulation that contributes to the establishment of epigenetic marks in the parental gametes (Reik & Walter, 2001). The mechanisms for gene imprinting are still not fully elucidated; however, it is believed that they involve epigenetic silencing through methylation of CpG-rich domains in a parent-specific manner during gametonenesis (Pfeifer, 2000). This phenomenon results in the preferential expression of specific genes from the allele inherited either from the father or from the mother. For example, the imprinted gene insulin-like growth factor 2 (Igf2), which was shown to play an important role in fetal development and growth, is exclusively expressed from the paternal allele; the maternally inherited allele for Igf2 is epigenetically silenced (Chao & D'Amore, 2008). Because of these epigenetically mediated allele-specific gene expressions, imprinted genes are believed to be especially susceptible to epigenetic dysregulation by environmental factors, such as nutrition, stress, and toxic agents. For example, it was shown that maternal exposure to methyl-deficient diets during pregnancy can alter the expression of imprinted genes (Bekdash, Zhang, & Sarkar, 2013; Waterland, Lin, Smith, & Jirtle, 2006). When these imprinting aberrations occur during early fetal development, they are often manifested as developmental and neurological disorders. Evidence shows that among the different organs, the brain is the most enriched tissue in imprinted genes (Prickett & Oakey, 2012) and, therefore, the most vulnerable to environmental perturbations (Jirtle & Skinner, 2007). Several research studies have reported that early-life exposure to environmental factors such as stress, drugs, and toxins can alter the epigenetic status of imprinted genes and other genes important to brain development and result in neurobehavioral deficiencies and psychiatric disorders (Jirtle & Skinner, 2007; Prickett & Oakey, 2012). Furthermore, it is suggested that certain inherited brain disorders such as Beckwith–Wiedemann syndrome, Rett syndrome, fragile X syndrome, and Angelman's syndrome arise from abnormal-specific imprinted genes (Kaminsky, Wang, & Petronis, 2006; Kantor, Shemer, & Razin, 2006; Weksberg, Shuman, & Smith, 2005).

In this review, we describe the most recent findings on transgenerational epigenetic inheritance, particularly in relation to brain disorders. We first discuss the mounting evidence that supports the transgenerational inheritance of environmentally induced epigenetic alterations and then we describe the epigenetic mechanisms involved in the alcohol-mediated neurobehavioral and cognitive deficiencies and their role in the transgenerational transmission of alcohol's deleterious effects on brain development and function. We conclude this review by arguing that understanding the implications of these environmentally induced transgenerational epigenetic changes will extend our knowledge on human disease susceptibility and ultimately lead to the development of new diagnostic and therapeutic strategies.

2 Epigenetics and Epigenetic Processes

Richard Goldschmidt, an integrative biologist, believed that early developmental exposure to events has as much impact as genetics on the determination of the adult phenotype (Goldschmidt, 1933). It is not until 1940 that the renowned embryologist Conrad Hal Waddington attempted to bridge both fields of genetics and embryology by being the first to coin the term “epigenetics.” Waddington described development as the path from genotype to phenotype and suggested that the mechanisms by which genes guide development or epigenetic, a process influenced by the surrounding environment, should be given the name of epigenetics. In his opinion, the epigenetic processes help to bridge the gap between environmental and genetic factors.

In recent years, “epigenetics” is referred to as the study of mechanisms involved in changes in genetic information and gene expression that are independent of any change in DNA sequence (i.e., mutations). This process serves to maintain different gene expression patterns during key developmental periods and contributes to the determination of different cell phenotypes. It also constitutes a dynamic process that helps translate environmental stimuli into changes in gene expression patterns (Jang & Serra, 2014; Jirtle et al., 2007; Reul, 2014).

Many epigenetic processes have been identified. We look at some of the epigenetic marks that consist of DNA methylation at the carbon-5 position of cytosine on CpG dinucleotides, histone proteins posttranslational modifications (HPTMs) at their N-terminal tails by methylation, acetylation, phosphorylation, ubiquitination, ADP-ribosylation, and sumoylation and interference of gene transcription by small noncoding RNAs (sncRNAs; Kugel & Goodrich, 2012). Epigenetic marks induce changes in chromatin structure and serve as docking sites for transcription factors (i.e., activators and repressors). They are specific to each gene and are dynamically regulated by various environmental conditions. In terms of gene activity, a condensed chromatin (heterochromatin) is generally repressed, whereas an open chromatin (euchromatin) is transcriptionally active and tends to be associated with distinct epigenetic signals. Heterochromatin is often associated with methylation of CpG dinucleotides, hypoacetylation of H3 and H4, and dimethylation/trimethylation of lysine 9 on H3 (H3K9Me2,3), whereas euchromatin is associated with hypomethylation of CpG dinucleotides, acetylation of H3 and H4, and dimethylation/trimethylation of lysine 4 on H3 (H3K4Me; Shukla et al., 2008). Another mechanism involved in modulating chromatin structure is the incorporation of nonallelic histone variants of H2A, H2B, and H3, and not H4, which replace preexisting conventional histones during development and differentiation (Bosch & Suau, 1995; Brandt et al., 1979; Margueron & Reinberg, 2010; Wunsch, Reinhardt, & Lough, 1991). This selective deposition of histone variants may become predominant in the differentiated cell (Pina & Suau, 1987a, 1987b; Wunsch et al., 1991).

Several enzymes are involved in these epigenetic processes. Histone acetyltransferases acetylate lysine residues on the N-terminal tail of histone proteins, decreasing its affinity for DNA and resulting in the relaxation of chromatin making it accessible to the transcription machinery. In contrast, histone deacetylases remove the acetyl...