Abstract
DNA methylation represents one form of epigenetic factors that can influence gene activities without a change in DNA sequence1. In mammals, methylation of DNA occurs at the C5 position of the cytosine residues, primarily at the CpG dinucleotides. A family of DNA methyltransferases carries out the covalent reaction of cytosine methylation. The first methylase gene, Dnmtl, encodes a maintenance DNA methyltransferase (Dnmtl, EC 2.1.1.37) which preferentially methylates hemi-methylated DNA produced after DNA replication2. Two newly discovered methylase genes, Dnmt3a and 3b, are the de novo methyltransferases that can methylate native DNA substrates3,4. The essential role for these enzymes in establishing and maintaining DNA methylation has been demonstrated by targeted mutation of DNA methyltransferases in mice. Mutant mice lacking either Dnmtl or Dnmt3a and 3b exhibit significant demethylation in the genome, and die at embryonic day (E) 8-10 just after gastrulation4-6. These results indicate that DNA methylation is essential for mammalian embryonic development. At the cellular level, DNA hypomethylation also perturbs the events of genomic imprinting, X-chromosome inactivation, and suppression of endogenous retroviruses7-10
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References
R. Jaenisch. DNA methylation and imprinting: why bother? Trends Genet. 13, 323–329 (1997).
T. Bestor, A. Laudano, R. Mattaliano, and V. Ingram. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J Mol Biol 203, 971–983 (1988).
M. Okano, S. Xie, and E. Li. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nature Genetics 19, 219–220 (1998).
M. Okano, D. W. Bell, D. A. Haber, and E. Li. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).
E. Li, T. Bestor, R. Jaenisch. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).
H. Lei, S. Oh, M. Okano, R. Juttermann, K. Goss, R. Jaenisch, and E. Li,. De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 122, 3195–3205 (1996).
E. Li, C. Beard, and R. Jaenisch. Role for DNA methylation in genomic imprinting. Nature 366, 362–365 (1993).
C. Beard, E. Li, and R. Jaenisch. Loss of methylation activates Xist in somatic but not in embryonic cells. Genes Dey 9, 2325–2334 (1995).
B. Panning, and R. Jaenisch. DNA hypomethylation can activate Xist expression and silence X-linked genes. Genes Dey 10, 1991–2002 (1996).
C. P. Walsh, J. R. Chaillet, and T. H. Bestor. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20, 116–117 (1998).
K. Goto, M. Numata, J. I. Komura, T. Ono, T. H. Bestor, and H. Kondo. Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation 56, 39–44 (1994).
P.J. Brooks, C. Marietta, and D. Goldman. DNA mismatch repair and DNA methylation in adult brain neurons. J Neurosci 16, 939–945 (1996).
J. M. Trasler, D. G. Trasler, T. H. Bestor, E. Li, and F. Ghibu. DNA methyltransferase in normal and Dnmtn/Dnmtn mouse embryos. Dey Dyn 206, 239–247 (1996).
K. Inano, I. Suetake, T. Ueda, Y. Miyake, M. Nakamura, M. Okada, and S. Tajima. Maintenance-type DNA methyltransferase is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J Biochem. 128, 315–321 (2000)
V. L. Wilson, R. A. Smith, S. Ma, and R. G. Cutler. Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262, 9948–9951 (1987)
R. Tawa, T. Ono, A. Kurishita, S. Okada, and S. Hirose. Changes of DNA methylation level during pre-and postnatal periods in mice. Differentiation 45, 44–48 (1990).
T. Ono T, Y. Uehara, A. Kurishita, R. Tawa, and H. Sakurai. Biological significance of DNA methylation in the ageing process. Age Ageing 22, S34–43 (1993).
R.E. Amir, I.B. Van Den Veyver, M. Wan M, C. Q. Tran, U. Francke, and H. Y. Zoghbi. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet 23, 185–188 (1999).
H. H. Ng, and A. Bird. DNA methylation and chromatin modification. Curr Opin Genet Dey 9, 158–163 (1999).
A.M. Kerr. A review of the respiratory disorder in the Rett syndrome. Brain Dev 14, 43–45 (Suppl) (1992).
D. D. Armstrong, J. K. Dunn, R. J. Schultz, D. A. Herbert, D. G. Glaze, and K. J. Motil. Organ growth in Rett syndrome, a postmortem examination analysis. Pediatr Neurol 20, 125–129 (1999).
L. Jackson-Grusby, C. Beard, R. Possemato, D. Fambrough, G. Csankovszki, J. Dausman, P. Lee, C. B. Wilson, E. Lander, and R. Jaenisch. Loss of Genomic Methylation cause p53-dependent apoptosis and epigenetic deregulation. Nature Genet. 27, 31–9 (2001).
B. Bates, M. Rios, A. Trumpp, C. Chen, G. Fan, J. M. Bishop, and R. Jaenisch. Neurotrophin-3 is required for proper cerebellar development. Nat Neurosci 2, 115–117 (1999).
A. Trumpp, M.J. Depew, J.L.R. Rubenstein, J. M. Bishop, and G. R. Martin. Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first banchial arch. Genes Dey 13, 3136–48 (1999).
J. F. Paton, J. M. Ramirez, and D. W. Richter. Functionally intact in vitro preparation generating respiratory activity in neonatal and mature mammals. Pflugers Arch 428, 250–260 (1994).
D. J. Withington-Wray, S. W. Mifflin, K. M. Spyer. Intracellular analysis of respiratory-modulated hypoglossal motoneurons in the cat. Neuroscience 25, 1041–1051 (1988).
T. Ono, Y. Ishiwata, N. Inaba, T. Kuroda, and YNakamura. Hypoglossal premotor neurons with rhythmical inspiratory-related activity in the cat, localization and projection to the phrenic nucleus. Exp Brain Res 98, 1–12 (1994).
W. St. John. Neurogenesis of patterns of automatic ventilatory activity. Progress in Neurobiol. 56, 97–117 (1998).
M. Gerard, L. Hernandez, R. Wevrick, and C. L. Stewart. Disruption of the mouse necdin gene results in early post-natal lethality. Nat Genet. 23, 199–202 (1999).
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Fan, G., Siniaia, M., Poon, CS., Jaenisch, R. (2001). Effect of Dna Hypomethylation on Neural Control of Respiration: A Genetic Model. In: Poon, CS., Kazemi, H. (eds) Frontiers in Modeling and Control of Breathing. Advances in Experimental Medicine and Biology, vol 499. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1375-9_30
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DOI: https://doi.org/10.1007/978-1-4615-1375-9_30
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