MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs

Eckersley-Maslin, Mélanie; Svensson, Valentine; Krueger, Christel; Stubbs, Thomas M.; Giehr, Pascal; Krueger, Felix; Miragaia, Ricardo J.; Kyriakopoulos, Charalampos; Berrens, Rebecca; Milagre, Inês; Walter, Jörn; Teichmann, Sarah A.; Reik, Wolf

doi:10.1016/j.celrep.2016.08.087

Cited by 192 publications

(279 citation statements)

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“…Indeed, transcripts of major and minor satellite repeats were dramatically elevated in GFP + cells (Figure S1F), as these repeats are normally repressed by DNA methylation. Our results are consistent with a recent report showing that 2C-like mESCs exhibit genome-wide DNA hypomethylation (Eckersley-Maslin et al, 2016). …”

Section: Resultssupporting

confidence: 94%

“…Indeed, in Zscan4-GFP reporter cells treated with the proteasome inhibitor MG132, Uhrf1 and Dnmt1 levels were largely maintained in GFP + cells (Figures 1H-J), indicating that they are degraded by the ubiquitin-proteasome system in 2C-like mESCs. While inhibition of protein synthesis may contribute to gene expression in 2C-like cells (Eckersley-Maslin et al, 2016; Hung et al, 2013), the highly variable changes of different proteins suggest that their turnover rates could be the major determinant of their levels. Taken together, our results suggest that failure to maintain DNA methylation, mainly due to Uhrf1 and Dnmt1 degradation, leads to severe hypomethylation in 2C-like mESCs.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, Eckersley-Maslin et al also reported DNA hypomethylation in 2C-like mESCs and speculated that inhibition of Dnmt1, Dnmt3a and Dnmt3b translation was responsible (Eckersley-Maslin et al, 2016). Our study extends their work in several aspects.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic studies have shown that disruption of either Dnmt1 or Dnmt3a/Dnmt3b in mESCs leads to dramatic telomere elongation by homologous recombination (Gonzalo et al, 2006). Interestingly, recent evidence suggests that 2C-like mESCs undergo drastic chromatin remodeling, including decondensation of heterochromatin and genome-wide DNA hypomethylation (Akiyama et al, 2015; Eckersley-Maslin et al, 2016; Ishiuchi et al, 2015). However, little is known about the molecular mechanisms involved in these chromatin changes, as well as the functional relevance of the changes in telomere regulation.…”

Section: Introductionmentioning

confidence: 99%

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Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells

et al. 2017

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SUMMARY Proper telomere length is essential for embryonic stem cell (ESC) self-renewal and pluripotency. Mouse ESCs (mESCs) sporadically convert to a transient totipotent state similar to that of two-cell (2C) embryos to recover shortened telomeres. Zscan4, which exhibits a burst of expression in 2C-like mESCs, is required for telomere extension in these cells. However, the mechanism by which Zscan4 extends telomeres remains elusive. Here, we show that Zscan4 facilitates telomere elongation by inducing global DNA demethylation through downregulation of Uhrf1 and Dnmt1, major components of the maintenance DNA methylation machinery. Mechanistically, Zscan4 recruits Uhrf1 and Dnmt1 and promotes their degradation that is dependent on the E3 ubiquitin ligase activity of Uhrf1. Importantly, blocking DNA demethylation prevents telomere elongation associated with Zscan4 expression, suggesting that DNA demethylation mediates the effect of Zscan4. Our results define a molecular pathway that contributes to the maintenance of telomere length homeostasis in mESCs.

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Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells

et al. 2017

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“…First used in geostatistics 31 , GP models have been applied to test for differential gene expression over time 32 , including the analysis of bifurcation points 26 , and general tests for temporal variability 25,[33][34][35] .…”

Section: Relationship To Prior Workmentioning

confidence: 99%

SpatialDE - Identification of spatially variable genes

Svensson

Teichmann

Stegle

2017

Preprint

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131

278

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Technological advances have enabled lowinput RNA-sequencing, paving the way for assaying transcriptome variation in spatial contexts, including in tissues. While the generation of spatially resolved transcriptome maps is increasingly feasible, computational methods for analysing the resulting data are not established. Existing analysis strategies either ignore the spatial component of gene expression variation, or require discretization of the cells into coarse grained groups.To address this, we have developed SpatialDE, a computational framework for identifying and characterizing spatially variable genes. Our method generalizes variable gene selection, as used in population-and single-cell studies, to spatial expression profiles. To illustrate the broad utility of our approach, we apply SpatialDE to spatial transcriptomics data, and to data from single cell methods based on multiplexed in situ hybridisation (SeqFISH and MERFISH). SpatialDE enables the statistically robust identification of spatially variable genes, thereby identifying genes with known disease implications, several of which are missed by c o n v e n t i o n a l v a r i a b l e g e n e s e l e c t i o n . Additionally, to enable gene-expressed based histology, SpatialDE implements a spatial gene clustering model which we call "automatic expression histology," allowing to classify genes into groups with distinct spatial patterns.Technological advances have helped to miniaturize and parallelize genomics, thereby enabling high-throughput transcriptome profiling from low quantities of starting material, including in single cells. Increased experimental throughput has also fostered new experimental designs, where the spatial context of gene expression variation can now be directly assayed, which is critical for characterizing complex tissue architectures in multicellular organisms. The spatial context of gene expression is crucial for determining functions and phenotypes of cells 1,2 . Spatial expression variation can reflect communication between adjacent cells, or can be caused by cells that migrate to specific locations in a tissue to perform their functions.Several experimental methods to measure gene expression levels in a spatial context have been established, which differ in resolution, accuracy and throughput. These include the computational integration of single cell RNAseq data with a spatial reference dataset 3,4 , careful collection and recording of spatial location of samples 5 , parallel profiling of mRNA using barcodes on a grid of known spatial locations [5][6][7] , and methods based on multiplexed in situ hybridization 8,9 or sequencing 10-12 .A first critical step in the analysis of the resulting datasets is to identify the genes that exhibit spatial variation across the tissue. However, existing approaches for identifying highly variable genes 13,14 , as in single-cell RNA-sequencing (scRNA-seq) studies, ignore the spatial location and hence do not measure spatial variability ( Figure 1A). Alternatively, researchers have applied ANO...

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Genome architecture and totipotency: An intertwined relation during early embryonic development

Olbrich

Ruíz

2022

BioEssays

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Chromosomes are not randomly packed and positioned into the nucleus but folded in higher‐order chromatin structures with defined functions. However, the genome of a fertilized embryo undergoes a dramatic epigenetic reprogramming characterized by extensive chromatin relaxation and the lack of a defined three‐dimensional structure. This reprogramming is followed by a slow genome refolding that gradually strengthens the chromatin architecture during preimplantation development. Interestingly, genome refolding during early development coincides with a progressive loss of developmental potential suggesting a link between chromatin organization and cell plasticity. In agreement, loss of chromatin architecture upon depletion of the insulator transcription factor CTCF in embryonic stem cells led to the upregulation of the transcriptional program found in totipotent cells of the embryo, those with the highest developmental potential. This essay will discuss the impact of genome folding in controlling the expression of transcriptional programs involved in early development and their plastic‐associated features.

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MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs

Cited by 192 publications

References 45 publications

Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells

Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells

SpatialDE - Identification of spatially variable genes

Genome architecture and totipotency: An intertwined relation during early embryonic development

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