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Frontiers in Biology

ISSN 1674-7984

ISSN 1674-7992(Online)

CN 11-5892/Q

Front Biol    2012, Vol. 7 Issue (6) : 485-494    https://doi.org/10.1007/s11515-012-9246-1
REVIEW
DNA methylation program during development
Feng C. ZHOU()
Department of Anatomy and Cell Biology, Stark Neuroscience Research Institute, Indiana University School Medicine, Indianapolis, IN 46202, USA
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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 epigenetics      neural development      5-hydroxymethylcytosine      epigenome      environmental factors      DNA demethylation     
Corresponding Author(s): ZHOU Feng C.,Email:imce100@iupui.edu   
Issue Date: 01 December 2012
 Cite this article:   
Feng C. ZHOU. DNA methylation program during development[J]. Front Biol, 2012, 7(6): 485-494.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-012-9246-1
https://academic.hep.com.cn/fib/EN/Y2012/V7/I6/485
Fig.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 um for a–d.
Fig.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 ventrodorsal progression of maturation is also occurred. 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.
Fig.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.
CategoryEnviron. factorsEpigenetic changesPhenotypesReferences
NutritionFood deprivationFolate, Choline,DNA methylationLow birthweight, obesity, Cardiovascular disease, diabetes(Kaati et al., 2002; Kahn et al., 2009; Stein et al., 2006; Lumey and Stein, 2009) (Food deprivation)(McKay et al., 2004; Mason and Choi, 2005) (FA)(Zeisel, 2007) (Choline)
StressDeprivation, separationDNA methylationAsthmaStress response, fearfulness(Caldji et al., 1998; Meaney and Szyf, 2005; Champagne and Curley, 2009; Caldji et al., 2011) (Stress response)(Chia et al., 2011) Oxidative stress (Wright, 2011) Stress & asthma
PollutantBPAPAHDioxinHypomethylationmiRNAAsthma, Obesity, Tumerigenesis, Breast cancer(Kundakovic and Champagne, 2011) (BPA);(Jeffy et al., 2002; Xu et al. 2011; Tang et al., 2012) (PAH); (Wu et al., 2004) (Dioxin)
Toxic agentLead, ArsenicPesticide (Vinclozolin),DNA methylation, histone modificationALS, Alzheimer’s Disease.Abnormalities (prostate, kidney, immune, testis) and tumors.(Pilsner et al., 2009; Callaghan et al., 2011; Bakulski et al., 2012) (lead);(Kile et al., 2012, Martinez et al., 2011) (arsenic);(Anway et al., 2006) (Vinclozolin
Substance of abuseAlcohol,TobaccoDNA methylation, Histone modificationGrowth retardation, neurodevelopmental deficit, birthweight reduction(Liu et al., 2009; Ouko et al., 2009; Govorko et al., 2012; Otero et al., 2012,) (alcohol);(Suter et al., 2011) (Tobacco)
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