Table of Contents

    Topic review

    Epigenetics

    Subjects: Genetics
    View times: 26

    Definition

    Changes in gene expression/phenotype without underlying DNA modification.

    1. Introduction

    Epigenetics refers to changes in phenotypes without changes in genotypes, a concept first described by Waddington in 1942[1]. Subsequent research has shown that epigenetic modifications can occur as a result of at least three different mechanisms: (i) genomic DNA methylation, (ii) modification of DNA interacting proteins, and (iii) microRNAs. Various types of genomic DNA (gDNA) methylation are known. The most important one is probably methylation of cytosine in the 5C position. This creates 5-Methylcytosine (5mC) via de novo methyltransferases (DNMTs), and the 5mC is then converted to 5hmC via ten-eleven translocation methylcytosine dioxygenase (TET) enzymes, where the C is followed by a guanine (G) and separated by a phosphate (CpG).

    Higher levels of DNA methylation lead to chromatin condensation, for example, as observed during X-chromosome inactivation transposon silencing and genomic imprinting[2]. Until recently, 5mC was thought to be a stable modification of DNA and was expected to remain unchanged throughout the life of a fully differentiated somatic cell. However, it has now been discovered that 5mC can be oxidized to 5hmC[3]. Recent studies have shown that the enrichment of 5hmC on the gene body has been associated with activation of transcription[3][4][5][6][7][8] and TET-mediated 5mC oxidation regulates the activity on the transcription start site (TSS)[4][9][10] and active enhancers. Epigenetic studies of human hearts have reported altered 5mC in chronic heart failure. However, our knowledge with regard to the underlying molecular mechanisms in CVD remains incomplete, despite the observation that DNA methylation appears to regulate CVD development.

    The entry is from 10.3390/ijms21239010

    References

    1. Waddington, C.H. The Epigenotpye; Endeavour: Sydney, Australia, 1942; pp. 18–20.
    2. Zachary D. Smith; Alexander Meissner; DNA methylation: roles in mammalian development. Nature Reviews Genetics 2013, 14, 204-220, 10.1038/nrg3354.
    3. Gabriella Ficz; Miguel R. Branco; Stefanie Seisenberger; Fátima Santos; Felix Krueger; Timothy A. Hore; C. Joana Marques; Simon Andrews; Wolf Reik; Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 2011, 473, 398-402, 10.1038/nature10008.
    4. Pastor, W.A.; Pape, U.J.; Huang, Y.; Henderson, H.R.; Lister, R.; Ko, M.; McLoughlin, E.M.; Brudno, Y.; Mahapatra, S.; Kapranov, P.; et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 2011, 473, 394–397.
    5. Gan, H.; Wen, L.; Liao, S.; Lin, X.; Ma, T.; Liu, J.; Song, C.X.; Wang, M.; He, C.; Han, C.; et al. Dynamics of 5-hydroxymethylcytosine during mouse spermatogenesis. Nat. Commun. 2013, 4, 1995.
    6. Szulwach, K.E.; Li, X.; Li, Y.; Song, C.X.; Wu, H.; Dai, Q.; Irier, H.; Upadhyay, A.K.; Gearing, M.; Levey, A.I.; et al. 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat. Neurosci. 2011, 14, 1607–1616.
    7. Ivanov, M.; Kals, M.; Kacevska, M.; Barragan, I.; Kasuga, K.; Rane, A.; Metspalu, A.; Milani, L.; Ingelman-Sundberg, M. Ontogeny, distribution and potential roles of 5-hydroxymethylcytosine in human liver function. Genome Biol. 2013, 14, R83.
    8. Tsagaratou, A.; Aijo, T.; Lio, C.W.; Yue, X.; Huang, Y.; Jacobsen, S.E.; Lahdesmaki, H.; Rao, A. Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation. Proc. Natl. Acad. Sci. USA 2014, 111, E3306–E3315.
    9. Wu, H.; D’Alessio, A.C.; Ito, S.; Wang, Z.; Cui, K.; Zhao, K.; Sun, Y.E.; Zhang, Y. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 2011, 25, 679–684.
    10. Szulwach, K.E.; Li, X.; Li, Y.; Song, C.X.; Han, J.W.; Kim, S.; Namburi, S.; Hermetz, K.; Kim, J.J.; Rudd, M.K.; et al. Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet. 2011, 7, e1002154.
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