Epigenome and chromatin structure in human embryonic stem cells undergoing differentiation

Bártová, Eva; Galiová, Gabriela; Krejčí, Jana; Harničárová, Andrea; Strašák, Luděk; Kozubek, Stanislav

doi:10.1002/dvdy.21773

Cited by 59 publications

(71 citation statements)

References 60 publications

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“…Similar to the EtoL domains on autosomes, the Xi in female mammals also becomes late replicating and moves toward the nuclear periphery upon inactivation (Heard and Disteche 2006;Bartova et al 2008), with a late-replicating X chromosome emerging in the post-implantation epiblast in mice (E5.8-E6.3) (Takagi et al 1982). Our results suggest that autosomal lineageindependent EtoL changes occur within a similar time frame in the post-implantation epiblast.…”

Section: Discussionsupporting

confidence: 55%

Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis

Hiratani

Ryba²,

Itoh³

et al. 2009

Genome Res.

303

444

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Differentiation of mouse embryonic stem cells (mESCs) is accompanied by changes in replication timing. To explore the relationship between replication timing and cell fate transitions, we constructed genome-wide replication-timing profiles of 22 independent mouse cell lines representing 10 stages of early mouse development, and transcription profiles for seven of these stages. Replication profiles were cell-type specific, with 45% of the genome exhibiting significant changes at some point during development that were generally coordinated with changes in transcription. Comparison of early and late epiblast cell culture models revealed a set of early-to-late replication switches completed at a stage equivalent to the postimplantation epiblast, prior to germ layer specification and down-regulation of key pluripotency transcription factors [POU5F1 (also known as OCT4)/NANOG/SOX2] and coinciding with the emergence of compact chromatin near the nuclear periphery. These changes were maintained in all subsequent lineages (lineage-independent) and involved a group of irreversibly down-regulated genes, at least some of which were repositioned closer to the nuclear periphery. Importantly, many genomic regions of partially reprogrammed induced pluripotent stem cells (piPSCs) failed to re-establish ESC-specific replication-timing and transcription programs. These regions were enriched for lineage-independent earlyto-late changes, which in female cells included the inactive X chromosome. Together, these results constitute a comprehensive ''fate map'' of replication-timing changes during early mouse development. Moreover, they support a model in which a distinct set of replication domains undergoes a form of ''autosomal Lyonization'' in the epiblast that is difficult to reprogram and coincides with an epigenetic commitment to differentiation prior to germ layer specification.

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Section: Discussionsupporting

confidence: 55%

Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis

Hiratani

Ryba²,

Itoh³

et al. 2009

Genome Res.

303

444

View full text Add to dashboard Cite

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“…Indeed, in most mouse and human cell types, centromeres show a preferential localization near the NL (Weierich et al 2003;Wiblin et al 2005). An exception to this is human ES cells (Wiblin et al 2005;Bartova et al 2008). Centromeres have a unique chromatin composition (Bergmann et al 2012), which may modulate NL interactions.…”

Section: Discussionmentioning

confidence: 99%

Constitutive nuclear lamina–genome interactions are highly conserved and associated with A/T-rich sequence

et al. 2012

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In metazoans, the nuclear lamina is thought to play an important role in the spatial organization of interphase chromosomes, by providing anchoring sites for large genomic segments named lamina-associated domains (LADs). Some of these LADs are cell-type specific, while many others appear constitutively associated with the lamina. Constitutive LADs (cLADs) may contribute to a basal chromosome architecture. By comparison of mouse and human lamina interaction maps, we find that the sizes and genomic positions of cLADs are strongly conserved. Moreover, cLADs are depleted of synteny breakpoints, pointing to evolutionary selective pressure to keep cLADs intact. Paradoxically, the overall sequence conservation is low for cLADs. Instead, cLADs are universally characterized by long stretches of DNA of high A/T content. Cell-type specific LADs also tend to adhere to this “A/T rule” in embryonic stem cells, but not in differentiated cells. This suggests that the A/T rule represents a default positioning mechanism that is locally overruled during lineage commitment. Analysis of paralogs suggests that during evolution changes in A/T content have driven the relocation of genes to and from the nuclear lamina, in tight association with changes in expression level. Taken together, these results reveal that the spatial organization of mammalian genomes is highly conserved and tightly linked to local nucleotide composition.

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“…5B, differentiated mESCs). However, during differentiation of hESCs, there was pronounced accumulation of H3K27me3 into foci [21] or at the inactive X chromosome in female genomes [22,23]. Here, we analyzed the male phenotype of mESCs; thus, we did not observe pronounced accumulation of H3K27me3 associated with the X chromosome inactivation (see Fig.…”

Section: H3k27me3 Is a Specific Marker Of Mesc Pluripotencymentioning

confidence: 95%

Differentiation-Independent Fluctuation of Pluripotency-Related Transcription Factors and Other Epigenetic Markers in Embryonic Stem Cell Colonies

Šustáčková

Legartová²,

Kozubek³

et al. 2012

Stem Cells and Development

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Embryonic stem cells (ESCs) maintain their pluripotency through high expression of pluripotency-related genes. Here, we show that differing levels of Oct4, Nanog, and c-myc proteins among the individual cells of mouse ESC (mESC) colonies and fluctuations in these levels do not disturb mESC pluripotency. Cells with strong expression of Oct4 had low levels of Nanog and c-myc proteins and vice versa. In addition, cells with high levels of Nanog tended to occupy interior regions of mESC colonies. In contrast, peripherally positioned cells within colonies had dense H3K27-trimethylation, especially at the nuclear periphery. We also observed distinct levels of endogenous and exogenous Oct4 in particular cell cycle phases. The highest levels of Oct4 occurred in G2 phase, which correlated with the pKi-67 nuclear pattern. Moreover, the Oct4 protein resided on mitotic chromosomes. We suggest that there must be an endogenous mechanism that prevents the induction of spontaneous differentiation, despite fluctuations in protein levels within an mESC colony. Based on the results presented here, it is likely that cells within a colony support each other in the maintenance of pluripotency.

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Epigenome and chromatin structure in human embryonic stem cells undergoing differentiation

Cited by 59 publications

References 60 publications

Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis

Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis

Constitutive nuclear lamina–genome interactions are highly conserved and associated with A/T-rich sequence

Differentiation-Independent Fluctuation of Pluripotency-Related Transcription Factors and Other Epigenetic Markers in Embryonic Stem Cell Colonies

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