scholarly journals DNA methyltransferase-3–dependent nonrandom template segregation in differentiating embryonic stem cells

2013 ◽  
Vol 203 (1) ◽  
pp. 73-85 ◽  
Author(s):  
Christian Elabd ◽  
Wendy Cousin ◽  
Robert Y. Chen ◽  
Marc S. Chooljian ◽  
Joey T. Pham ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Molecular Mechanism ◽  
Cell Fate ◽  
Dna Methyltransferase ◽  
Daughter Cell ◽  
De Novo ◽  
Embryonic Stem ◽  
Fundamental Property ◽  
Dna Strands

Asymmetry of cell fate is one fundamental property of stem cells, in which one daughter cell self-renews, whereas the other differentiates. Evidence of nonrandom template segregation (NRTS) of chromosomes during asymmetric cell divisions in phylogenetically divergent organisms, such as plants, fungi, and mammals, has already been shown. However, before this current work, asymmetric inheritance of chromatids has never been demonstrated in differentiating embryonic stem cells (ESCs), and its molecular mechanism has remained unknown. Our results unambiguously demonstrate NRTS in asymmetrically dividing, differentiating human and mouse ESCs. Moreover, we show that NRTS is dependent on DNA methylation and on Dnmt3 (DNA methyltransferase-3), indicating a molecular mechanism that regulates this phenomenon. Furthermore, our data support the hypothesis that retention of chromatids with the “old” template DNA preserves the epigenetic memory of cell fate, whereas localization of “new” DNA strands and de novo DNA methyltransferase to the lineage-destined daughter cell facilitates epigenetic adaptation to a new cell fate.

De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells

Development ◽  
1996 ◽  
Vol 122 (10) ◽  
pp. 3195-3205 ◽  
Author(s):  
H. Lei ◽  
S.P. Oh ◽  
M. Okano ◽  
R. Juttermann ◽  
K.A. Goss ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Mammalian Cells ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Embryonic Stem ◽  
Cytosine Methyltransferase ◽  
Methyl Cytosine ◽  
Methylation Activity ◽  
De Novo Methylation

It has been a controversial issue as to how many DNA cytosine methyltransferase mammalian cells have and whether de novo methylation and maintenance methylation activities are encoded by a single gene or two different genes. To address these questions, we have generated a null mutation of the only known mammalian DNA methyltransferase gene through homologous recombination in mouse embryonic stem cells and found that the development of the homozygous embryos is arrested prior to the 8-somite stage. Surprisingly, the null mutant embryonic stem cells are viable and contain low but stable levels of methyl cytosine and methyltransferase activity, suggesting the existence of a second DNA methyltransferase in mammalian cells. Further studies indicate that de novo methylation activity is not impaired by the mutation as integrated provirus DNA in MoMuLV-infected homozygous embryonic stem cells become methylated at a similar rate as in wild-type cells. Differentiation of mutant cells results in further reduction of methyl cytosine levels, consistent with the de novo methylation activity being down regulated in differentiated cells. These results provide the first evidence that an independently encoded DNA methyltransferase is present in mammalian cells which is capable of de novo methylating cellular and viral DNA in vivo.

scholarly journals DNMT3B shapes the mCA landscape and regulates mCG for promoter bivalency in human embryonic stem cells

2019 ◽  
Vol 47 (14) ◽  
pp. 7460-7475 ◽  
Author(s):  
Hong Kee Tan ◽  
Chan-Shuo Wu ◽  
Jia Li ◽  
Zi Hui Tan ◽  
Jordan R Hoffman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Embryonic Stem ◽  
Distribution Profile ◽  
Pwwp Domain ◽  
The Common ◽  
On Chip

Abstract DNMT3B is known as a de novo DNA methyltransferase. However, its preferential target sites for DNA methylation are largely unknown. Our analysis on ChIP-seq experiment in human embryonic stem cells (hESC) revealed that DNMT3B, mCA and H3K36me3 share the same genomic distribution profile. Deletion of DNMT3B or its histone-interacting domain (PWWP) demolished mCA in hESCs, suggesting that PWWP domain of DNMT3B directs the formation of mCA landscape. In contrast to the common presumption that PWWP guides DNMT3B-mediated mCG deposition, we found that deleting PWWP does not affect the mCG landscape. Nonetheless, DNMT3B knockout led to the formation of 2985 de novo hypomethylated regions at annotated promoter sites. Upon knockout, most of these promoters gain the bivalent marks, H3K4me3 and H3K27me3. We call them spurious bivalent promoters. Gene ontology analysis associated spurious bivalent promoters with development and cell differentiation. Overall, we found the importance of DNMT3B for shaping the mCA landscape and for maintaining the fidelity of the bivalent promoters in hESCs.

scholarly journals Reduced Genomic Cytosine Methylation and Defective Cellular Differentiation in Embryonic Stem Cells Lacking CpG Binding Protein

2005 ◽  
Vol 25 (12) ◽  
pp. 4881-4891 ◽  
Author(s):  
Diana L. Carlone ◽  
Jeong-Heon Lee ◽  
Suzanne R. L. Young ◽  
Erika Dobrota ◽  
Jill Sergesketter Butler ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Dna Methyltransferase ◽  
Cellular Differentiation ◽  
Cytosine Methylation ◽  
Epigenetic Modification ◽  
Binding Protein ◽  
Embryonic Stem ◽  
Growth Media ◽  
Methyltransferase Activity

ABSTRACT Cytosine methylation at CpG dinucleotides is a critical epigenetic modification of mammalian genomes. CpG binding protein (CGBP) exhibits a unique DNA-binding specificity for unmethylated CpG motifs and is essential for early murine development. Embryonic stem cell lines deficient for CGBP were generated to further examine CGBP function. CGBP − / − cells are viable but show an increased rate of apoptosis and are unable to achieve in vitro differentiation following removal of leukemia inhibitory factor from the growth media. Instead, CGBP − / − embryonic stem cells remain undifferentiated as revealed by persistent expression of the pluripotent markers Oct4 and alkaline phosphatase. CGBP − / − cells exhibit a 60 to 80% decrease in global cytosine methylation, including hypo-methylation of repetitive elements, single-copy genes, and imprinted genes. Total DNA methyltransferase activity is reduced by 30 to 60% in CGBP − / − cells, and expression of the maintenance DNA methyltransferase 1 protein is similarly reduced. However, de novo DNA methyltransferase activity is normal. Nearly all aspects of the pleiotropic CGBP − / − phenotype are rescued by introduction of a CGBP expression vector. Hence, CGBP is essential for normal epigenetic modification of the genome by cytosine methylation and for cellular differentiation, consistent with the requirement for CGBP during early mammalian development.

scholarly journals TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells

2017 ◽  
Vol 50 (1) ◽  
pp. 83-95 ◽  
Author(s):  
Nipun Verma ◽  
Heng Pan ◽  
Louis C. Doré ◽  
Abhijit Shukla ◽  
Qing V. Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
De Novo ◽  
Embryonic Stem ◽  
Tet Proteins ◽  
De Novo Methylation

scholarly journals Regulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells

PLoS Biology ◽  
2009 ◽  
Vol 7 (7) ◽  
pp. e1000149 ◽  
Author(s):  
Tibor Kalmar ◽  
Chea Lim ◽  
Penelope Hayward ◽  
Silvia Muñoz-Descalzo ◽  
Jennifer Nichols ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Embryonic Stem ◽  
Cell Fate Decisions ◽  
Nanog Expression ◽  
Mediate Cell

scholarly journals Developmental remodelling of non-CG methylation at satellite DNA repeats

2020 ◽  
Vol 48 (22) ◽  
pp. 12675-12688 ◽  
Author(s):  
Samuel E Ross ◽  
Allegra Angeloni ◽  
Fan-Suo Geng ◽  
Alex de Mendoza ◽  
Ozren Bogdanovic
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Transcriptional Repression ◽  
Dna Methyltransferase ◽  
Embryonic Stem ◽  
Dna Methyltransferases ◽  
Dna Repeats ◽  
Satellite Repeats ◽  
Cg Dinucleotides ◽  
The Brain

Abstract In vertebrates, DNA methylation predominantly occurs at CG dinucleotides however, widespread non-CG methylation (mCH) has been reported in mammalian embryonic stem cells and in the brain. In mammals, mCH is found at CAC trinucleotides in the nervous system, where it is associated with transcriptional repression, and at CAG trinucleotides in embryonic stem cells, where it positively correlates with transcription. Moreover, CAC methylation appears to be a conserved feature of adult vertebrate brains. Unlike any of those methylation signatures, here we describe a novel form of mCH that occurs in the TGCT context within zebrafish mosaic satellite repeats. TGCT methylation is inherited from both male and female gametes, remodelled during mid-blastula transition, and re-established during gastrulation in all embryonic layers. Moreover, we identify DNA methyltransferase 3ba (Dnmt3ba) as the primary enzyme responsible for the deposition of this mCH mark. Finally, we observe that TGCT-methylated repeats are specifically associated with H3K9me3-marked heterochromatin suggestive of a functional interplay between these two gene-regulatory marks. Altogether, this work provides insight into a novel form of vertebrate mCH and highlights the substrate diversity of vertebrate DNA methyltransferases.

scholarly journals Targeting of De Novo DNA Methylation Throughout the Oct-4 Gene Regulatory Region in Differentiating Embryonic Stem Cells

PLoS ONE ◽  
2010 ◽  
Vol 5 (4) ◽  
pp. e9937 ◽  
Author(s):  
Rodoniki Athanasiadou ◽  
Dina de Sousa ◽  
Kevin Myant ◽  
Cara Merusi ◽  
Irina Stancheva ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
De Novo ◽  
Regulatory Region ◽  
Embryonic Stem ◽  
Gene Regulatory

Human embryonic stem cells and cardiac cell fate

2009 ◽  
Vol 218 (3) ◽  
pp. 455-459 ◽  
Author(s):  
David Nury ◽  
Tui Neri ◽  
Michel Pucéat
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Cardiac Cell
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