title: DNA methyltransferase-3-dependent nonrandom template segregation in differentiating embryonic stem cells.
abstract: 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.
authors.affiliation: Department of Bioengineering, 2 Stem Cell Center, and 3 QB3 Institute, University of California, Berkeley, Berkeley, CA 94720.
authors.forename: Christian
authors.initials: C
authors.lastname: Elabd
authors.forename: Wendy
authors.initials: W
authors.lastname: Cousin
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Chen
authors.forename: Marc S
authors.initials: MS
authors.lastname: Chooljian
authors.forename: Joey T
authors.initials: JT
authors.lastname: Pham
authors.forename: Irina M
authors.initials: IM
authors.lastname: Conboy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Conboy
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D020090:Chromosome Segregation; D018920:Coculture Techniques; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D058732:Embryoid Bodies / Q000201:enzymology; D053595:Embryonic Stem Cells / Q000201:enzymology*; D044127:Epigenesis, Genetic; D061252:Feeder Cells; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D013997:Time Factors; D059008:Time-Lapse Imaging; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D006655:Histone Deacetylases; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human