Preimplantation expression of the somatic form of Dnmt1 suggests a role in the inheritance of genomic imprints

Cirio, M. Cecilia; Ratnam, Sarayu; Ding, Feng; Reinhart, Bonnie; Navara, Christopher S.; Chaillet, J. Richard

doi:10.1186/1471-213x-8-9

Cited by 115 publications

(134 citation statements)

References 28 publications

(48 reference statements)

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“…This maternal-effect DNMT1o function can be restored by oocyte-derived DNMT1s protein, but not restored by embryo-derived DNMT1o expressed from a modified endogenous Dnmt1 allele (6,14). These findings are further support for sequence-specific DNMT1 activity during preimplantation development, and suggest that the developmental source of the protein (oocyte versus embryo) determines this specificity.…”

supporting

confidence: 65%

“…Oocyte-derived DNMT1o and embryo-derived DNMT1s are both present in nuclei of 8-cell blastomeres, yet only the oocytederived protein can maintain imprinted DMD methylation at this stage (5,6). This maternal-effect DNMT1o function can be restored by oocyte-derived DNMT1s protein, but not restored by embryo-derived DNMT1o expressed from a modified endogenous Dnmt1 allele (6,14).…”

mentioning

confidence: 89%

“…Following fertilization DMD methylation is maintained (inherited) during preimplantation development by the combined action of different isoforms of the DNMT1 cytosine methyltransferase (5)(6)(7)(8). The M r 175,000 DNMT1o form is synthesized in the oocyte and maintains methylation during preimplantation development (5,9), whereas the M r 190,000 DNMT1s form is synthesized both in the oocyte and in the early embryo and this form also functions in preimplantation embryos (6). Along with this maintenance of DMD methylation is a significant reduction in the level of global (non-DMD) methylation (10,11).…”

mentioning

confidence: 99%

“…Methylation is placed on DMD sequences in the maternal and paternal germ lines by the DNMT3a cytosine methyltransferase (3,4). Following fertilization DMD methylation is maintained (inherited) during preimplantation development by the combined action of different isoforms of the DNMT1 cytosine methyltransferase (5)(6)(7)(8). The M r 175,000 DNMT1o form is synthesized in the oocyte and maintains methylation during preimplantation development (5,9), whereas the M r 190,000 DNMT1s form is synthesized both in the oocyte and in the early embryo and this form also functions in preimplantation embryos (6).…”

mentioning

confidence: 99%

“…Detection of DNMT1s proteins was performed using an immunoblot assay as previously described (6). Affinity-purified rabbit anti-DNMT1 antibody UPT82 was used at a 1:1,000 dilution.…”

mentioning

confidence: 99%

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Identification of a region of the DNMT1 methyltransferase that regulates the maintenance of genomic imprints

Borowczyk

Mohan

D’Aiuto

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Reprogramming of DNA methylation patterns during mammalian preimplantation development involves the concurrent maintenance of methylation on differentially methylated domains (DMDs) of imprinted genes and a marked reduction of global (non-DMD) genomic methylation. In the developing mammalian embryo, one allele of a DMD is unmethylated, and the opposite parental allele is methylated, having inherited this methylation from the parental gamete. The maintenance of DMDs is important for monoallelic imprinted gene expression and normal development of the embryo. Because the DNMT1 cytosine methyltransferase governs maintenance methylation in mammals, rearrangements of non-DMD, but not DMD methylation in preimplantation embryos suggest that the preimplantation DNMT1-dependent maintenance mechanism specifically targets DMD sequences. We explored this possibility using an engineered mouse ES cell line to screen for mutant DNMT1 proteins that protect against the loss of DMD and/or global (non-DMD) methylation in the absence of the wild-type endogenous DNMT1 methyltransferase. We identified DNMT1 mutants that were defective in maintenance of either DMD and/or non-DMD methylation. Among these, one mutant maintained non-DMD methylation but not imprinted DMD methylation and another mutant maintained just DMD methylation. The mutated amino acids of these mutants reside in a mammal-specific, disordered region near the amino terminus of DNMT1. These findings suggest that DNMT1 participates in epigenetic reprogramming through its ability to distinguish different categories of methylated sequences.epigenetic ͉ imprinting ͉ methylase ͉ methylation ͉ reprogramming G enomic imprinting is a mammalian epigenetic process that distinguishes maternal and paternal alleles to ensure parent-specific (monoallelic) expression of Ϸ80 imprinted genes (1). The molecular basis of this process is de novo methylation during gametogenesis and maintenance methylation during embryogenesis; this sequence of activities leads to the generation of imprinted DMDs (2). Methylation is placed on DMD sequences in the maternal and paternal germ lines by the DNMT3a cytosine methyltransferase (3, 4). Following fertilization DMD methylation is maintained (inherited) during preimplantation development by the combined action of different isoforms of the DNMT1 cytosine methyltransferase (5-8). The M r 175,000 DNMT1o form is synthesized in the oocyte and maintains methylation during preimplantation development (5, 9), whereas the M r 190,000 DNMT1s form is synthesized both in the oocyte and in the early embryo and this form also functions in preimplantation embryos (6). Along with this maintenance of DMD methylation is a significant reduction in the level of global (non-DMD) methylation (10, 11). The concurrent inheritance of DMD methylation and reduction of global methylation rearranges the genome's methylation patterns just before the formation of pluripotent embryo stem cells (12).Maintenance of DMD methylation in the presence of a reduction in the average level of g...

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supporting

confidence: 65%

mentioning

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…Detection of DNMT1s proteins was performed using an immunoblot assay as previously described (6). Affinity-purified rabbit anti-DNMT1 antibody UPT82 was used at a 1:1,000 dilution.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Identification of a region of the DNMT1 methyltransferase that regulates the maintenance of genomic imprints

Borowczyk

Mohan

D’Aiuto

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Epigenetic Reprogramming in Mammalian Development

Lepikhov

Arand

Wossidlo

et al. 2012

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Epidemiology of acephalus/acardius monozygotic twins: New insights into an epigenetic causal hypothesis

Martı́nez-Frı́as

2009

American J of Med Genetics Pt A

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Apart from a series of 10 acephalus/acardius (Ac/Ac) cases described from a pathological point of view, and the analysis of a review of published cases, we have been unable to find any epidemiological studies on Ac/Ac. Using data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), we present here what seems to be the first epidemiological analysis of a consecutive series of the Ac/Ac type of monozygotic twins (MZT). Among a total of 2,281,604 consecutive births, 11 cases of Ac/Ac MZT were detected, giving a frequency of 0.48 per 100,000 births. However, we consider the period 1980-1985 as the baseline for our data, as in this period voluntary termination of pregnancy was not possible in Spain, and the frequency of Ac/Ac MZT was 0.49 per 100,000 births. Nonetheless, this frequency should be considered as a minimal estimation. The characteristics of these Ac/Ac cases indicate that they are more frequent in males (sex ratio 2.67). In addition, gestational age in Ac/Ac cases was 2.41 and 3.12 weeks lower than in malformed and control twins, respectively. Similarly, their mothers are 4.54 and 4.68 years younger than mothers of separate malformed and control twins, respectively. To understand the biological basis behind the occurrence of MZT in the context of recent observations, we evaluate the hypothesis that the epigenetic processes involved in the early cleavage of the embryo, and in blastocyst formation during development, may be implicated in twinning.

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Preimplantation expression of the somatic form of Dnmt1 suggests a role in the inheritance of genomic imprints

Cited by 115 publications

References 28 publications

Identification of a region of the DNMT1 methyltransferase that regulates the maintenance of genomic imprints

Identification of a region of the DNMT1 methyltransferase that regulates the maintenance of genomic imprints

Epigenetic Reprogramming in Mammalian Development

Epidemiology of acephalus/acardius monozygotic twins: New insights into an epigenetic causal hypothesis

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