DNA methylation in development

Early embryonic development is a very precise and complicated process. When a sperm meets an egg, a series of well-orchestrated changes take place, which end up with distinct types of cells that make up an organism. Cells start from a pluripotent state and differentiate without changes in DNA sequence. A differentiated cell shares the same DNA sequence with the zygote from which it is descended (mammalian B and T cells being an exception). The diverse functions of different cells are due to tissue-specific patterns of gene expression, which are established during development; once the fates of the cells are decided, they will be maintained faithfully through cell divisions. Hence it is reasonable to assert that development is, by definition, an epigenetic process (Reik, 2007). The specific gene expression programs in differentiated cells are regulated by a more flexible system, which dynamically switches on and off the genes for maintaining homeostasis or responding to environmental changes. Epigenetics is defined as “the study of heritable changes in genome function that occur without alterations to the DNA sequence” (Probst, et al., 2009). Epigenetics has been suggested as the key regulatory system in early development. Mechanistically, epigenetic regulation involves the covalent modification of chromatin components such as DNA methylation and histone modifications (acetylation, methylation and phosphorylation are the best characterized). Short and long non-coding RNAs are also part of the epigenetic regulatory system because of their role in targeting the chromatin modifications within the genome (Hawkins & Morris, 2008; Morris, 2009a). DNA methylation at the cytosine residue of CpG dinucleotides is the most studied epigenetic modification in mammals. Its effects on genome function underlie a number of physiological phenomena such as genomic imprinting and X chromosome inactivation, and it also contributes to the genesis of human cancers and to aging. CpG methylation was the only known chemical modification of mammalian genomic DNA with an epigenetic role before the discovery of 5-hydroxymethylcytosine that will be discussed later (Haluskova, 2010; Ohgane, et al., 2008). CpG methylation is stable, heritable and reversible, which fulfils the requirement for a dynamic regulation system for development. DNA methylation is most vulnerable to the environment during early development, because the genome methylation pattern is established during this stage and the DNA synthetic rate is very high in the early embryo. In mammals, proper DNA methylation is essential for normal development. Aberrant methylation patterns are involved in various developmental pathological phenomena and even diseases in adult life that are known under the rubric: the Developmental Origin of Health and Disease (DOHaD) (Waterland & Michels, 2007). In this chapter, we will discuss the biochemistry of DNA CpG methylation including the enzymes catalyzing the process and the controversial pathways of DNA demethylation. The dynamics of DNA methylation in early development will be covered as well as the role of methylation in cell-lineage determination, imprinting and the genesis of germ cells. We will also review the evidence supporting the importance of DNA methylation in DOHaD.