Transcription of IAP endogenous retroviruses is constrained by cytosine methylation

Walsh, Colum P.; Chaillet, J. Richard; Bestor, TH

doi:10.1038/2413

Cited by 994 publications

(753 citation statements)

References 9 publications

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“…This was further supported by sequence data obtained from the IAP-Notch1 hybrid transcripts: all cloned hybrids varied in their IAP portion suggesting that they originate from different IAP elements (Supplementary Figure 3). IAP expression is suppressed by DNA methylation and was found to be significantly elevated in demethylated ES cells and embryos (Walsh et al, 1998). Mice carrying the hypomorphic allele Dnmt1 Chip/À exhibit genomewide DNA hypomethylation in all tissues and throughout embryonic development ), yet we could not find any significant increase in IAP expression in a variety of tissues from the preleukemic Dnmt1 Chip/À mice or in MOV-induced lymphomas (Figure 4).…”

mentioning

confidence: 75%

Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice

et al. 2007

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Genomewide DNA hypomethylation is a consistent finding in human tumors, but the importance of this change for human tumorigenesis remains an open question. We have previously reported that mice carrying a hypomorphic allele for the maintenance DNA methyltransferase (Dnmt1 chip/À ) are hypomethylated and develop thymic lymphomas, demonstrating that genomewide DNA hypomethylation can induce tumors. Hypomethylated cells exhibit inherent chromosomal instability, which is revealed in the lymphomas as a consistent trisomy of chromosome 15. We now report another aspect of the molecular basis for tumor development upon DNA hypomethylation. Seven out of 16 hypomethylationinduced lymphomas were found to contain an intracisternal A particle (IAP) somatic insertion in the middle of the Notch1 genomic locus, leading to generation of an oncogenic form of Notch1 in the tumors. This finding suggests that the molecular basis for hypomethylationinduced tumors in this model involves chromosomal instability events accompanied by activation of endogenous retroviral elements. Our findings validate the proposed role of DNA methylation in suppression of transposable elements in mammalian cells and demonstrate the importance of DNA methylation for normal cell function as well as the potential consequences of spontaneously occurring or chemically induced DNA hypomethylation.

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confidence: 75%

Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice

et al. 2007

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“…To investigate whether global methylation was affected in mutant mice, we examined the methylation of IAP elements (Walsh et al, 1998). Genomic DNA from forebrain, cerebellum, and heart samples from adult mice were digested with HpaII, which recognizes 5ЈCCGG3Ј targets and is sensitive to methylation at the internal cytosine.…”

Section: Cre1 Mutant Micementioning

confidence: 99%

“…Methylation analysis. A: Methylation at intracisternal A particle elements (Walsh et al, 1998). Southern blot of genomic DNA from heterozygous (H, Dnmt3a 2lox/ϩ ;Nes-Cre1) and mutant (M, Dnmt3a 2lox/1lox ;Nes-Cre1) mice digested with HpaII, a methylation sensitive enzyme that cleaves at CCGGs.…”

Section: Dnmt3a/nes-cre1 Mutant Mice Appear Normalmentioning

confidence: 99%

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Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

Nguyen¹,

Meletis²,

Fu³

et al. 2007

Developmental Dynamics

175

134

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DNA methylation is an epigenetic mechanism involved in gene regulation and implicated in the functioning of the nervous system. The de novo DNA methyltransferase Dnmt3a is expressed in neurons, but its specific role has not been clarified. Dnmt3a is activated around embryonic day 10.5 in mouse neuronal precursor cells and remains active in postmitotic neurons in the adult. We assessed the role of neuronal Dnmt3a by conditional gene targeting. Mice lacking functional Dnmt3a in the nervous system were born healthy, but degenerated in adulthood and died prematurely. Mutant mice were hypoactive, walked abnormally, and underperformed on tests of neuromuscular function and motor coordination. Loss of Dnmt3a also led to fewer motor neurons in the hypoglossal nucleus and more fragmented endplates in neuromuscular junctions of the diaphragm muscle. Our results implicate a role for Dnmt3a in the neuromuscular control of motor movement.

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“…Long repeats including LINE-1 elements are normally heavily DNA-methylated (Woodcock et al, 1988;Crowther et al, 1991;Woodcock et al, 1997), a feature of heterochromatin. DNA methylation (and heterochromatin in general) has been reported to suppress homologous recombination (Pàldi et al, 1995;Maloisel and Rossignol, 1998;Schnable et al, 1998;Fu et al, 2002;Yao et al, 2002;Yamada et al, 2004;Myers et al, 2005) as well as transposition (Yoder et al, 1997;Walsh et al, 1998;Hirochika et al, 2000;Robertson, 2001;Bird, 2002;Kato et al, 2003). Accordingly, reports of deletions caused by homologous recombination between LINE-1 elements are rare (Segal et al, 1999) except in cancers (Florl and Schulz, 2003) where LINE-1 elements are frequently hypomethylated (Santourlidis et al, 1999;Takai et al, 2000;Ehrlich, 2002;Carnell and Goodman, 2003;Florl et al, 2004;Roman-Gomez et al, 2005).…”

Section: Non-random Repeat Distributions Via Natural Selectionmentioning

confidence: 99%

Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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Housekeeping genes are expressed across a wide variety of tissues. Since repetitive sequences have been reported to influence the expression of individual genes, we employed a novel approach to determine whether housekeeping genes can be distinguished from tissue-specific genes their repetitive sequence context. We show that Alu elements are more highly concentrated around housekeeping genes while various longer (>400-bp) repetitive sequences ("repeats"), including Long Interspersed Nuclear Element 1 (LINE-1) elements, are excluded from these regions. We further show that isochore membership does not distinguish housekeeping genes from tissue-specific genes and that repetitive sequence environment distinguishes housekeeping genes from tissue-specific genes in every isochore. The distinct repetitive sequence environment, in combination with other previously published sequence properties of housekeeping genes, were used to develop a method of predicting housekeeping genes on the basis of DNA sequence alone. Using expression across tissue types as a measure of success, we demonstrate that repetitive sequence environment is by far the most important sequence feature identified to date for distinguishing housekeeping genes.

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Transcription of IAP endogenous retroviruses is constrained by cytosine methylation

Cited by 994 publications

References 9 publications

Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice

Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice

Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan

Repetitive sequence environment distinguishes housekeeping genes

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