Collaborative rewiring of the pluripotency network by chromatin and signalling modulating pathways

Tran, Khoa; Jackson, Steven A.; Olufs, Zachariah P. G.; Zaidan, Nur Zafirah; Leng, Ning; Kendziorski, Christina; Roy, Sushmita; Sridharan, Rupa

doi:10.1038/ncomms7188

Cited by 36 publications

(50 citation statements)

References 59 publications

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“…Indeed ascorbic acid‐induced demethylation might compensate in this setting for the ability of Nanog to recruit Tet2 to crucial target genes during reprogramming, including Esrrb . In agreement, Esrrb reactivation in pre‐iPS cells was shown to require ascorbic acid . Esrrb reactivation, bypassed by its ectopic expression, could be in this light the rate limiting step in the late stages of reprogramming.…”

Section: Esrrb: Marker and Effector In Somatic Cell Reprogrammingmentioning

confidence: 71%

Esrrb, an estrogen‐related receptor involved in early development, pluripotency, and reprogramming

2017

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Estrogen-related receptor b (Esrrb) is part of a family of three orphan nuclear receptors with broad expression profiles and a generic function in regulating energy metabolism in mammals. However, Esrrb performs specific functions during early mouse development, in pluripotent and multipotent populations of the embryo as well as in primordial germ cells. Moreover, Esrrb also impinges upon the control of self-renewal in embryo-derived stem cells and enhances reprogramming. Here, we review the function of Esrrb with special emphasis on its role in pluripotency. Esrrb activity at crucial regulatory elements of the pluripotency network, coupled with its role as a mitotic bookmarking factor and the ability to reset cellular metabolism, might explain its potent functions in ensuring the stability of pluripotency and driving the late stages of reprogramming. Hence, we argue that Esrrb represents a key addition to the pantheon of transcription factors sustaining pluripotent stem cell identity in mice. Understanding the mechanisms governing the interplay between different estrogen-related receptors (ERRs) and their specificity of action may clarify the role these factors play during preimplantation development and in pluripotent cells in both mouse and humans.

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Section: Esrrb: Marker and Effector In Somatic Cell Reprogrammingmentioning

confidence: 71%

Esrrb, an estrogen‐related receptor involved in early development, pluripotency, and reprogramming

2017

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“…Although the prominent role of Ooep is in oocytes, it is also expressed in ES cells and coordinately regulated with Dppa5a during reprogramming (Tashiro et al 2010;Tran et al 2015). This coordinated regulation during reprogramming may be due to regulation of both genes by the same cluster of enhancers surrounding Dppa5a, characterized here by enhancer deletion analysis.…”

Section: Wwwgenomeorgmentioning

confidence: 88%

Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes

et al. 2016

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Transcriptional enhancers are critical for maintaining cell-type-specific gene expression and driving cell fate changes during development. Highly transcribed genes are often associated with a cluster of individual enhancers such as those found in locus control regions. Recently, these have been termed stretch enhancers or super-enhancers, which have been predicted to regulate critical cell identity genes. We employed a CRISPR/Cas9-mediated deletion approach to study the function of several enhancer clusters (ECs) and isolated enhancers in mouse embryonic stem (ES) cells. Our results reveal that the effect of deleting ECs, also classified as ES cell super-enhancers, is highly variable, resulting in target gene expression reductions ranging from 12% to as much as 92%. Partial deletions of these ECs which removed only one enhancer or a subcluster of enhancers revealed partially redundant control of the regulated gene by multiple enhancers within the larger cluster. Many highly transcribed genes in ES cells are not associated with a super-enhancer; furthermore, super-enhancer predictions ignore 81% of the potentially active regulatory elements predicted by cobinding of five or more pluripotency-associated transcription factors. Deletion of these additional enhancer regions revealed their robust regulatory role in gene transcription. In addition, select super-enhancers and enhancers were identified that regulated clusters of paralogous genes. We conclude that, whereas robust transcriptional output can be achieved by an isolated enhancer, clusters of enhancers acting on a common target gene act in a partially redundant manner to fine tune transcriptional output of their target genes.

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“…In addition, the log-normal distribution of the reprogramming rate used in our paper is only one out of infinitely many possibilities based on the current data. A recent paper (Tran et al, 2015) also showed that combining ascorbic acid (AA) and 2i (MAP kinase and GSK inhibitors) can synergize reprogramming. Even though our modeling does not directly model the first passage time, it is not difficult to use our model to study such data (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Probabilistic Modeling of Reprogramming to Induced Pluripotent Stem Cells

et al. 2016

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Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is typically an inefficient and asynchronous process. A variety of technological efforts have been made to accelerate and/or synchronize this process. In order to define a unified framework to study and compare the dynamics of reprogramming under different conditions, we developed an in silico analysis platform based on mathematical modeling. Our approach takes into account the variability in experimental results stemming from probabilistic growth and death of cells and potentially heterogeneous reprogramming rates. We suggested that reprogramming driven by the Yamanaka factors alone is a more heterogeneous process possibly due to cell-specific reprogramming rates, which could be homogenized by the addition of additional factors. We validated our approach using publicly available reprogramming data sets, including data on early reprogramming dynamics as well as cell count data, and thus demonstrated the general utility and predictive power of our methodology for investigating reprogramming and other cell fate change systems.

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Collaborative rewiring of the pluripotency network by chromatin and signalling modulating pathways

Cited by 36 publications

References 59 publications

Esrrb, an estrogen‐related receptor involved in early development, pluripotency, and reprogramming

Esrrb, an estrogen‐related receptor involved in early development, pluripotency, and reprogramming

Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes

Probabilistic Modeling of Reprogramming to Induced Pluripotent Stem Cells

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