DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei

  title={DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei},
  author={Stina Simonsson and J. B. Gurdon},
  journal={Nature Cell Biology},
Nuclear transplantation experiments in amphibia and mammals have shown that oocyte and egg cytoplasm can extensively reprogram somatic cell nuclei with new patterns of gene expression and new pathways of cell differentiation; however, very little is known about the molecular mechanism of nuclear reprogramming. Here we have used nuclear and DNA transfer from mammalian somatic cells to analyse the mechanism of activation of the stem cell marker gene oct4 by Xenopus oocytes. We find that the… 

Gradual DNA demethylation of the Oct4 promoter in cloned mouse embryos

The results suggest that the Oct4 gene, as compared to the other pluripotency regulators, needs to undergo extensive demethylation during nuclear reprogramming, and that the failure of such dem methylation is associated with inefficient development of cloned somatic cell embryos.

The cytoplasm of mouse germinal vesicle stage oocytes can enhance somatic cell nuclear reprogramming

It is found that the GV oocyte cytoplasm could remodel somatic cell nuclei, completely demethylate histone H3 at lysine 9 and partially deacetylate histones 9 and 14, which could facilitate cloning technology and is useful for research on the mechanisms involved in histone de acetylation and demethylation.

Epigenetic memory of active gene transcription is inherited through somatic cell nuclear transfer.

  • R. K. NgJ. Gurdon
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
It is concluded that an epigenetic memory is established in differentiating somatic cells and applies to genes that are in a transcriptionally active state in some nuclear transplant embryos.

Epigenetic reprogramming and DNA demethylation

This study examines changes in DNA methylation that are induced at imprinted loci and pluripotency-associated genes when somatic cells are fused with either mouse embryonic stem (ES) or embryonic germ (EG) cells and provides evidence that Tet proteins are dispensable for pluripotent reprogramming using CRISPR-Cas9 genome editing to abrogate the expression of both Tet1 and Tet2.

Evaluation in mammalian oocytes of gene transcripts linked to epigenetic reprogramming.

Some of the mechanisms that the oocyte may employ to reprogram a foreign genome either in form of a spermatozoa or a somatic nucleus are elucidated for the first time and may be of importance for advancing the fields of stem cell research and regenerative medicine.

Epigenetic marks in somatic chromatin are remodelled to resemble pluripotent nuclei by amphibian oocyte extracts

It is demonstrated that axolotl oocyte extracts are a useful tool for studying epigenetic remodelling of somatic cells to a stem cell configuration, and for elucidating oocyte specific mechanisms of nuclear reprogramming.

Active tissue-specific DNA demethylation conferred by somatic cell nuclei in stable heterokaryons

It is reported that differentiated mesodermal somatic cells can confer tissue-specific changes in DNA methylation on epidermal progenitor cells after fusion in stable multinucleate heterokaryons, suggesting the possibility of directing the reprogramming of readily available postnatal human progenitors cells toward specific tissue cell types.

Examination of DNA methyltransferase expression in cloned embryos reveals an essential role for Dnmt1 in bovine development

An essential role for Dnmt1 during bovine preimplantation development is indicated, and proper transcriptional reprogramming of this gene family in SCNT embryos is suggested, to better understand the epigenetic events underlying SCNT reprograming.



DNA methylation represses transcription in vivo

An embryo-specific element from the CpG island sequence upstream of Aprt is characterized that can protect itself from de novo methylation in transgenic mice as well as reduce methylation of flanking sequences.

DNA methylation at promoter regions regulates the timing of gene activation in Xenopus laevis embryos.

The results suggest that DNA methylation has a role in regulating the timing of gene activation at MBT in Xenopus laevis embryos, which may account for the altered patterns of gene expression that occur in these embryos that are depleted of the maintenance methyltransferase enzyme.

Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei

It is posited that cloned embryos derived from differentiated cell nuclei fail to establish a population of truly pluripotent embryonic cells because of faulty reactivation of key embryonic genes such as Oct4.

Chromatin remodeling in nuclear cloning.

Studies involving the modification of chromatin elements such as selective uptake or release of binding proteins, covalent histone modifications including acetylation and methylation, and DNA methylation should provide significant insight into the molecular mechanisms of nuclear dedifferentiation and redifferentiation in oocyte cytoplasm.

Epigenetic Control of Mouse Oct-4 Gene Expression in Embryonic Stem Cells and Trophoblast Stem Cells*

It is proposed that the epigenetic mechanism, consisting of DNA methylation and chromatin remodeling, underlies the developmental stage- and cell type-specific mechanism of Oct-4 gene expression.

Epigenetic reprogramming in early mammalian development and following somatic nuclear transfer.

Reversible disassembly of somatic nucleoli by the germ cell proteins FRGY2a and FRGY2b

The results show that a single protein fragment can trigger reversible disassembly of the complex nucleolar structure, and it is shown that the carboxy-terminal domain of FRGY2a, which localizes to the nucleoli, is sufficient for nucleolar disassembly in transfected cells.

Oct4 distribution and level in mouse clones: consequences for pluripotency.

The quality of GFP signals in blastocysts correlated with the ability to generate outgrowths that maintain GFP expression and the frequency of embryonic stem (ES) cell derivation, and the variations observed in Oct4 levels alone account for the majority of failures currently observed for somatic cell cloning.

Molecular Mechanisms of Gene Silencing Mediated by DNA Methylation

It is demonstrated that a few methylated cytosines can inhibit a flanking promoter but a threshold of modified sites is required to organize a stable, diffusible chromatin structure.