DNA methylation program during development

Abstract

DNA methylation is a key epigenetic mark when occurring in the promoter and enhancer regions regulates the accessibility of the binding protein and gene transcription. DNA methylation is inheritable and can be de novo-synthesized, erased and reinstated, making it arguably one of the most dynamic upstream regulators for gene expression and the most influential pacer for development. Recent progress has demonstrated that two forms of cytosine methylation and two pathways for demethylation constitute ample complexity for an instructional program for orchestrated gene expression and development. The forum of the current discussion and review are whether there is such a program, if so what the DNA methylation program entails, and what environment can change the DNA methylation program. The translational implication of the DNA methylation program is also proposed.

Keywords: 5-hydroxymethylcytosine; DNA demethylation; environmental factors; epigenetics; epigenome; neural development.

Figure 1

The DNA methylation program shows spatiotemporal distribution of the immunocytochemical staining (brown diaminobenzidine) of methylation marks, 5mC (a) and 5hmC (b), and their demethylated forms, 5caC (c) and 5fC (d) in the neural tube at approximately gestation day 10 old embryo. There is a clear dorsoventral gradation in the neural tube in which DNA-methylation program (both 5mC and 5hmC, and their demethylation form 5fC and 5caC in the ventral is ahead of that of the dorsal. The progress of methylation gradations are parallel with the progression of differentiation gradation shown by immunostained cellular retinoic acid binding protein (Crabp, e) and nestin (f). D: dorsal aspect, V: ventral aspect. 5mC: 5methylcytosine, 5hmC: 5hydroxylmethylcytosine, 5fC: 5formylcytosine, 5caC: 5carboxylcytosine. Vertical scale bar = 50 μm for a–d.

Figure 2

The progression of embryonic development has a distinct neural axial and ventrodorsal gradations. The hindbrain is developed first and the differentiation (Diff) progressed rostrally and caudally in the neural tube axis. In cross section, a ventral to dorsal progression of maturation also occurs. This maturation gradation is evident in the order of neural tube closure in both axial and ventrodorsal progression. It is also evident by many phenotypic markers e.g. nestin, Crabp, neu-N and Map2 (Zhou et al., 2011). The progression of maturation is overlapped with progression of DMP (DNA methylation program) of many DNA methylation marks as well as with histone codes. D: dorsal aspect, V: ventral aspect. Arrows indicate direction of progression of neural tube closure, DMP and differentiation.

Figure 3

The epigenome is not static but dynamic, and not only tissue specific but are also cell-type specific; its making during development is not random but programmed in orderly manner. The epigneome is now believed permeable and subject to changes. During or after establishment of the epigenome, environment factors such as nutrition, stress, toxin, pollutant, and abusive substance can through changing epigenetics to alter the epigenome.