Chromosomal Instability and Tumors Promoted by DNA Hypomethylation

Eden, Amir; Gaudet, François; Waghmare, Alpana; Jaenisch, Rudolf

doi:10.1126/science.1083557

Cited by 1,240 publications

(850 citation statements)

References 5 publications

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“…Mice carrying a hypomorphic DNMT1 allele have reduced DNMT1 expression up to 10% of the wild type levels and have a substantial genome-wide hypomethylation in all tissues. These mice develop aggressive T cell lymphomas that display a high frequency of chromosome 15 trisomy [21,89]. Hypomethylated cells carrying a hypomorphic allele of DNMT1 undergo an increase in loss of heterozygosity (LOH) rate, in consistent with the hypothesis that hypomethylation promotes tumor development in NPcis mice by increasing the rate of LOH [89].…”

Section: Abe Rrant Epigenetic Changes Of Dna and Chromatin In Human Dsupporting

confidence: 75%

“…These mice develop aggressive T cell lymphomas that display a high frequency of chromosome 15 trisomy [21,89]. Hypomethylated cells carrying a hypomorphic allele of DNMT1 undergo an increase in loss of heterozygosity (LOH) rate, in consistent with the hypothesis that hypomethylation promotes tumor development in NPcis mice by increasing the rate of LOH [89]. In addition, patients having DNMT3B gene mutated in the germ line are prone to chromosome instability [21].…”

Section: Abe Rrant Epigenetic Changes Of Dna and Chromatin In Human Dsupporting

confidence: 69%

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Dynamic and reversibility of heterochromatic gene silencing in human disease

et al. 2005

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In eukaryotic organisms cellular fate and tissue specific gene expression are regulated by the activity of proteins known as transcription factors that by interacting with specific DNA sequences direct the activation or repression of target genes. The post genomic era has shown that transcription factors are not the unique key regulators of gene expression. Epigenetic mechanisms such as DNA methylation, post-translational modifications of histone proteins, remodeling of nucleosomes and expression of small regulatory RNAs also contribute to regulation of gene expression, determination of cell and tissue specificity and assurance of inheritance of gene expression levels. The relevant contribution of epigenetic mechanisms to a proper cellular function is highlighted by the effects of their deregulation that cooperate with genetic alterations to the development of various diseases and to the establishment and progression of tumors.

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Section: Abe Rrant Epigenetic Changes Of Dna and Chromatin In Human Dsupporting

confidence: 75%

Section: Abe Rrant Epigenetic Changes Of Dna and Chromatin In Human Dsupporting

confidence: 69%

Dynamic and reversibility of heterochromatic gene silencing in human disease

et al. 2005

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“…DNMT3b germline mutation are responsible for the immunodeficiency centromeric instability-facial anomalies (ICF) syndrome, the cancer risk of which is not known, while no DNMT1 germline mutation in any genetic syndrome has so far been reported. Results obtained in mouse models again reflect the need for well-adjusted DNMT function to maintain cellular homeostasis: DNMT1 knockout mice are 'protected' against the development of colorectal adenomas when crossed with APC-deficient mice (Laird et al, 1995), but they are 'prone' to develop lymphomas in the context of mice susceptible to this type of neoplasia (Eden et al, 2003). These latter results may be explained if lymphomas rely predominantly on chromosomal instability dependent on genomic DNA hypomethylation, while colon tumours rely more on the CpG island methylation status of tumour-suppressor genes (Yamada et al, 2005).…”

Section: Estellermentioning

confidence: 83%

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

2006

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Cancer is nowadays recognised as a genetic and epigenetic disease. Much effort has been devoted in the last 30 years to the elucidation of the 'classical' oncogenes and tumour-suppressor genes involved in malignant cell transformation. However, since the acceptance that major disruption of DNA methylation, histone modification and chromatin compartments are a common hallmark of human cancer, epigenetics has come to the fore in cancer research. One piece is still missing from the story: are the epigenetic genes themselves driving forces on the road to tumorigenesis? We are in the early stages of finding the answer, and the data are beginning to appear: knockout mice defective in DNA methyltransferases, methyl-CpG-binding proteins and histone methyltransferases strongly affect the risk of cancer onset; somatic mutations, homozygous deletions and methylation-associated silencing of histone acetyltransferases, histone methyltransferases and chromatin remodelling factors are being found in human tumours; and the first cancer-prone families arising from germline mutations in epigenetic genes, such as hSNF5/INI1, have been described. Even more importantly, all these 'new' oncogenes and tumour-suppressor genes provide novel molecular targets for designed therapies, and the first DNA-demethylating agents and inhibitors of histone deacetylases are reaching the bedside of patients with haematological malignancies.

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“…They also showed that this reduction occurred at DNA repetitive regions that are undermethylated. Such hypomethylation of repetitive sequences has previously been linked to chromosomal instabilities (Ehrlich, 2002;Eden et al, 2003). A thorough investigation into loss/reduction of H4K16Ac in human tumors remains to be performed as the above study leaves some outstanding questions: Does the reduction in acetylation lead to hypomethylation or vice versa?…”

Section: A Link With Cancermentioning

confidence: 99%

Males absent on the first (MOF): from flies to humans

2007

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Histone modifications such as acetylation, methylation and phosphorylation have been implicated in fundamental cellular processes such as epigenetic regulation of gene expression, organization of chromatin structure, chromosome segregation, DNA replication and DNA repair. Males absent on the first (MOF) is responsible for acetylating histone H4 at lysine 16 (H4K16) and is a key component of the MSL complex required for dosage compensation in Drosophila. The human ortholog of MOF (hMOF) has the same substrate specificity and recent purification of the human and Drosophila MOF complexes showed that these complexes were also highly conserved through evolution. Several studies have shown that loss of hMOF in mammalian cells leads to a number of different phenotypes; a G 2 /M cell cycle arrest, nuclear morphological defects, spontaneous chromosomal aberrations, reduced transcription of certain genes and an impaired DNA repair response upon ionizing irradiation. Moreover, hMOF is involved in ATM activation in response to DNA damage and acetylation of p53 by hMOF influences the cell's decision to undergo apoptosis instead of a cell cycle arrest. These data, highlighting hMOF as an important component of many cellular processes, as well as links between hMOF and cancer will be discussed.

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Chromosomal Instability and Tumors Promoted by DNA Hypomethylation

Cited by 1,240 publications

References 5 publications

Dynamic and reversibility of heterochromatic gene silencing in human disease

Dynamic and reversibility of heterochromatic gene silencing in human disease

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

Males absent on the first (MOF): from flies to humans

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