Targeted mutation of the DNA methyltransferase gene results in embryonic lethality

Li, En; Bestor, Timothy H.; Jaenisch, Rudolf

doi:10.1016/0092-8674(92)90611-f

Cited by 3,589 publications

(2,520 citation statements)

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“…All of the primary leukemia samples expressed a transcript containing aberrant splicing between exons 9 and 13 as originally observed, confirming that the expression of these novel mRNAs was not due to an artifact of in vitro culture. Notably, there was expression of at least one of the three wild-type DNMT3B transcripts in all of the tumor cell line-derived cDNAs as well as in all of the primary leukemia samples, in keeping with previous data that complete loss of DNMT3B activity is incompatible with viability (Li et al, 1992;Okano et al, 1999).…”

Section: Cancer Cells Express Aberrant Dnmt3b Transcriptssupporting

confidence: 89%

“…Both DNMT3A and DNMT3B catalyse de novo methylation of DNA sequences (Li, 2002). Each of these three enzymes is essential for life, since homozygous knockout alleles of Dnmt1 and Dnmt3b cause embryonic lethality in mice, and mice with homozygous knockout alleles of Dnmt3a die several weeks after birth (Li et al, 1992;Okano et al, 1999). Dnmt1À/À embryonic stem cells display extensive demethylation of endogenous retroviral DNA (Li et al, 1992), and murine embryonic stem cells lacking Dnmt3b demonstrate hypomethylation of minor satellite sequences (Okano et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Each of these three enzymes is essential for life, since homozygous knockout alleles of Dnmt1 and Dnmt3b cause embryonic lethality in mice, and mice with homozygous knockout alleles of Dnmt3a die several weeks after birth (Li et al, 1992;Okano et al, 1999). Dnmt1À/À embryonic stem cells display extensive demethylation of endogenous retroviral DNA (Li et al, 1992), and murine embryonic stem cells lacking Dnmt3b demonstrate hypomethylation of minor satellite sequences (Okano et al, 1999). Patients with a rare autosomal recessive syndrome, the immunodeficiency, centromere instability, facial anomalies (ICF) syndrome, have germline mutations in the DNMT3B gene (Hansen et al, 1999;Xu et al, 1999;Shirohzu et al, 2002), and lymphocytes from affected individuals display hypomethylation of repetitive DNA sequences.…”

Section: Introductionmentioning

confidence: 99%

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Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

et al. 2007

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Cancer cells display an altered distribution of DNA methylation relative to normal cells. Certain tumor suppressor gene promoters are hypermethylated and transcriptionally inactivated, whereas repetitive DNA is hypomethylated and transcriptionally active. Little is understood about how the abnormal DNA methylation patterns of cancer cells are established and maintained. Here, we identify over 20 DNMT3B transcripts from many cancer cell lines and primary acute leukemia cells that contain aberrant splicing at the 5 0 end of the gene, encoding truncated proteins lacking the C-terminal catalytic domain. Many of these aberrant transcripts retain intron sequences. Although the aberrant transcripts represent a minority of the DNMT3B transcripts present, Western blot analysis demonstrates truncated DNMT3B isoforms in the nuclear protein extracts of cancer cells. To test if expression of a truncated DNMT3B protein could alter the DNA methylation patterns within cells, we expressed DNMT3B7, the most frequently expressed aberrant transcript, in 293 cells. DNMT3B7-expressing 293 cells have altered gene expression as identified by microarray analysis. Some of these changes in gene expression correlate with altered DNA methylation of corresponding CpG islands. These results suggest that truncated DNMT3B proteins could play a role in the abnormal distribution of DNA methylation found in cancer cells.

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Section: Cancer Cells Express Aberrant Dnmt3b Transcriptssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

et al. 2007

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“…A number of studies have been conducted to evaluate the biological consequences of losing DNMT1 activity. In 1992 Li et al [13] have shown that insertion of a mutant DNMT1 gene into mouse germ line produces a recessive lethal phenotype. The m5C levels in homozygous mutant mouse ES cells were one-third of that in wild-type cells but the cells were still viable.…”

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confidence: 99%

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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“…Histone acetylation in gene promoter/enhancer regions is generally correlated with transcriptional activation (Hattori et al, 2004;Tomikawa et al, 2006). Methylation of DNA is essential for mammalian development and is associated with gene silencing in conjunction with histone core modifications, probably through chromatin remodeling (Jones et al, 1998;Li et al, 1992). For example, histone acetylation in the Kiss1 gene, that is upregulated in the anteroventra periventricular nucleus of brain, enhanced chromatic loop formation of Kiss1 promoter and Kiss1 gene enhancer, resulting in an increase in Kiss1 genespecific expression (Tomikawa et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Differential Promoter Methylation and Histone Modification Contribute to the Brain Specific Expression of the Mouse Mbu-1 Gene

Kim

Kang

Kim

2012

Molecules and Cells

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Mbu-1 (Csrnp-3) is a mouse gene that was identified in our previous study as showing highly restricted expression to the central nervous system. In this study, to elucidate the regulatory mechanism for tissue specificity of the gene, epigenetic approaches that identify the profiles of CpG methylation, as well as histone modifications at the promoter region were conducted. Methylation-specific PCR revealed that the CpG sites in brain tissues from embryo to adult stages showed virtually no methylation (0.052-0.67%). Lung (9.0%) and pancreas (3.0%) also showed lower levels. Other tissues such as liver, kidney, and heart showed much higher methylation levels ranging from approximately 39-93%. Treatment of 5-aza-2′-deoxycytidine (5-Aza-dC) significantly decreased promoter methylation, reactivating Mbu-1 expression in NG108-15 and Neuro-2a neuronal cells. Chromatin immunoprecipitation assay revealed that 5-Aza-dC decreased levels of acetylated H3K9 and methylated H3K4, and increased methylated H3K9. This result indicates that CpG methylation converses with histone modifications in an opposing sense of regulating Mbu-1 expression.

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Targeted mutation of the DNA methyltransferase gene results in embryonic lethality

Cited by 3,589 publications

References 46 publications

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

Dynamic and reversibility of heterochromatic gene silencing in human disease

Differential Promoter Methylation and Histone Modification Contribute to the Brain Specific Expression of the Mouse Mbu-1 Gene

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