DNA methylation and human disease

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Robertson, K. D. DNA methylation and chromatin — unraveling the tangled web. Oncogene 21, 5361–5379 (2002).

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Mayer, W., Niveleau, A., Walter, J., Fundele, R. & Haaf, T. Demethylation of the zygotic paternal genome. Nature 403, 501–502 (2000). This paper demonstrates that active demethylation occurs during embryonic development in the absence of cell division.

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Bird, A. CpG-rich islands and the function of DNA methylation. Nature 321, 209–213 (1986).

Song, F. et al. Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc. Natl Acad. Sci. USA 102, 3336–3341 (2005).

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Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999). References 10 and 11 describe in detail the detrimental effects that loss of DNA methylation has on mouse embryonic development.

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Issa, J. -P. CpG island methylator phenotype in cancer. Nature Rev. Cancer 4, 988–993 (2004).

Chan, A. O.- O. et al. CpG island methylation in aberrant crypt foci of the colorectum. Am. J. Pathol. 160, 1823–1830 (2002).

Costello, J. F. et al. Aberrant CpG-island methylation has a non-random and tumor-type-specific patterns. Nature Genet. 25, 132–138 (2000). This paper represents one of the most comprehensive genome-wide scans for aberrant methylation in cancer and demonstrates just how widespread the defects are.

Laird, P. W. The power and the promise of DNA methylation markers. Nature Rev. Cancer 3, 253–266 (2003).

Feinberg, A. P., Cui, H. & Ohlsson, R. DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms. Sem. Canc. Biol. 12, 389–398 (2002).

Reik, W. & Walter, J. Genomic imprinting: parental influence on the genome. Nature Rev. Genet. 2, 21–32 (2001).

Klenova, E. M., Morse, H. C., Ohlsson, R. & Lobanenkov, V. V. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Sem. Canc. Biol. 449, 1–16 (2002).

Kanduri, C. et al. Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr. Biol. 10, 853–856 (2000). This paper shows that CTCF binding is methylation sensitive and provides important mechanistic insights into how cells distinguish between maternal and paternal alleles.

Thakur, N. et al. An antisense RNA regulates the bidirectional silencing property of the Kcnq1 imprinting control region. Mol. Cell. Biol. 24, 7855–7862 (2004).

Schoenherr, C. J., Levorse, J. M. & Tilghman, S. M. CTCF maintains differential methylation at the Igf2/H19 locus. Nature Genet. 33, 66–69 (2003).

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De Baun, M. R., Niemitz, E. L. & Feinberg, A. P. Association of in vitro fertilization with Beckwith–Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am. J. Hum. Genet. 72, 156–160 (2003). References 34–37 show that in vitro culturing of embryos can lead to epigenetic defects in animals and that this might also have a role in humans.

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Cui, H. et al. Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Res. 61, 4947–4950 (2001).

Nakagawa, H. et al. Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc. Natl Acad. Sci. USA 98, 591–596 (2001).

Cui, H. et al. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res. 62, 6442–6446 (2002).

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Lee, M. P. et al. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KvLQT1, occurs frequently in Beckwith–Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proc. Natl Acad. Sci. USA 96, 5203–5208 (1999).

Kanduri, C. et al. A differentially methylated imprinting control region within the Kcnq1 locus harbors a methylation-sensitive chromatin insulator. J. Biol. Chem. 277, 18106–18110 (2002).

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Weksberg, R. et al. Tumor development in the Beckwith–Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum. Mol. Genet. 10, 2989–3000 (2001).

Diaz-Meyer, N. et al. Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith–Wiedemann syndrome. J. Med. Genet. 40, 797–801 (2005).

Goldstone, A. P. Prader–Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol. Metab. 15, 12–20 (2004).

Nicholls, R. D. & Knepper, J. L. Genome organization, function, and imprinting in Prader–Willi and Angelman syndromes. Annu. Rev. Genomics Hum. Genet. 2, 153–175 (2001).

Sutcliffe, J. S. et al. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nature Genet. 8, 52–58 (1994).

Runte, M. et al. Comprehensive methylation analysis in typical and atypical PWS and AS patients with normal biparental chromosomes 15. Eur. J. Hum. Genet. 9, 519–526 (2001).

Runte, M. et al. The IC-SNURF–SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum. Mol. Genet. 10, 2687–2700 (2001).

Gerard, G., Hernandez, L., Wevrick, R. & Stewart, C. L. Disruption of the mouse necdin gene results in early post-natal lethality. Nature Genet. 23, 199–202 (1999).

Tsai, T. F., Jiang, Y. H., Bressler, J., Armstrong, D. & Beaudet, A. L. Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth retardation and partial lethality and provides evidence for a gene contributing to Prader–Willi syndrome. Nature Genet. 8, 1357–1364 (1999).

Saitoh, S. & Wada, T. Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader–Willi syndrome. Am. J. Hum. Genet. 66, 1958–1962 (2000).

Lossie, A. C. et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J. Med. Genet. 38, 834–845 (2001).

Buiting, K., Lich, C., Cottrell, S., Barnicoat, A. & Horsthemke, B. A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp. Hum. Genet. 105, 665–666 (1999).

Lalande, M. Imprints of disease at GNAS1. J. Clin. Inves. 107, 793–794 (2001).

Liu, J., Nealon, J. G. & Weinstein, L. S. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB. Hum. Mol. Genet. 14, 95–102 (2005).

Hayward, B. E. et al. Imprinting of the G s α gene GNAS1 in the pathology of acromegaly. J. Clin. Inves. 107, R31–R36 (2001).

Temple, I. K. & Shield, J. P. H. Transient neonatal diabetes, a disorder of imprinting. J. Med. Genet. 39, 872–875 (2002).

Arima, T. et al. A conserved imprinting control region at the HYMAI/ZAC domain is implicated in transient neonatal diabetes mellitus. Hum. Mol. Genet. 10, 1475–1483 (2001).

Morison, I. M. & Reeve, A. E. A catalogue of imprinted genes and parent-of-origin effects in humans and animals. Hum. Mol. Genet. 7, 1599–1609 (1998). An excellent review detailing all known disorders in humans and animals that have a parent-of-origin bias.

Lewis, A. & Murrell, A. Genomic imprinting: CTCF protects the boundaries. Curr. Biol. 14, R284–R286 (2004).

Everett, C. M. & Wood, N. W. Trinucleotide repeats and neurodegenerative disease. Brain 127, 2385–2405 (2004).

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Crawford, D. C., Acuna, J. M. & Sherman, S. L. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet. Med. 3, 359–371 (2001).

Sutherland, G. R. Rare fragile sites. Cytogenet. Genome Res. 100, 77–84 (2003).

Jin, P., Alisch, R. S. & Warren, S. T. RNA and microRNAs in fragile X mental retardation. Nature Cell Biol. 6, 1048–1053 (2004).

Hagerman, R. J. et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57, 127–130 (2001).

Oberle, I. et al. Instability of a 550-base pair segment and abnormal methylation in fragile X syndrome. Science 252, 1097–1102 (1991).

Coffee, B., Zhang, F., Ceman, S., Warren, S. T. & Reines, D. Histone modifications depict an aberrantly heterochromatinized FMR1 gene in fragile X syndrome. Am. J. Hum. Genet. 71, 923–932 (2002).

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Rijkers, T. et al. FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients. J. Med. Genet. 41, 826–836 (2004).

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Filippova, G. N. et al. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nature Genet. 28, 335–343 (2001).

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Quddus, J. et al. Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J. Clin. Inves. 92, 38–53 (1993).

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Loukinov, D. I. et al. BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc. Natl Acad. Sci. USA 99, 6806–6811 (2002). The first in-depth characterization of the CTCF paralogue BORIS and a demonstration of the mutually exclusive expression of these two proteins in normal tissues.

Verdel, A. et al. RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303, 672–676 (2004).

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