Epigenomic Comparison Reveals Activation of “Seed” Enhancers during Transition from Naive to Primed Pluripotency

Factor, Daniel C.; Corradin, Olivia; Zentner, Gabriel E.; Saiakhova, Alina; Song, Lingyun; Chenoweth, Josh G.; McKay, Ronald D.G.; Crawford, Gregory E.; Scacheri, Peter C.; Tesar, Paul J.

doi:10.1016/j.stem.2014.05.005

Cited by 147 publications

(185 citation statements)

References 45 publications

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“…Only a few sites showed increased OCT4 occupancy ( n = 3,532) in Esrrb‐GFP negative cells, and these had detectable OCT4 binding in Esrrb‐GFP high cells (Fig 5B). In apparent contradiction to this, activation of new enhancers has been reported to occur during the dismantling of naïve pluripotency (Buecker et al , 2014; Factor et al , 2014; Yang et al , 2014; Cao et al , 2018; Yan et al , 2018). However, such regulatory elements were not identified here, possibly because they are regulated exclusively by lineage‐specific TFs missing from our analysis.…”

Section: Discussionmentioning

confidence: 99%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanoglow cells. Independent Esrrb reporter lines demonstrate that Esrrbnegative ESCs cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. ChIP‐Seq identifies different regulatory element classes that bind both OCT4 and NANOG in Esrrbpositive cells. Class I elements lose NANOG and OCT4 binding in Esrrbnegative ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, Class II elements retain OCT4 but not NANOG binding in ESRRB‐negative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.

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Section: Discussionmentioning

confidence: 99%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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“…An epigenome comparison of naive ESCs and primed EpiSCs revealed the presence of "seed" enhancers, which are dormant in ESCs but activated in EpiSCs to take over primary transcriptional control of genes that are similarly expressed in either cell state (7). By this definition, the proximal enhancer E of Tet1 is neither a seed nor a "poised" enhancer because total Tet1 RNA levels were much higher in ESCs than in EpiSCs; moreover, enhancer E demonstrated in vitro activity in both cell states (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…This pluripotent state is dependent on the master transcription factors Oct4, Sox2, and Nanog (OSN), which often bind cooperatively at target sites on enhancers. In early mammalian development, the triad of OSN, by binding to different enhancers, orchestrates two states of pluripotency, the "naive" and "primed" conditions resembling the pre-and postimplantation epiblasts, respectively (6,7). Furthermore, OSN together with Klf4, Esrrb, and Mediator coactivator, all highly expressed in naive ESCs, densely occupy extended domains of enhancer clusters, named "superenhancers," which are associated with genes that play major roles in ESC identity (8).…”

mentioning

confidence: 99%

Dynamic Switching of Active Promoter and Enhancer Domains Regulates Tet1 and Tet2 Expression during Cell State Transitions between Pluripotency and Differentiation

Sohni

Bartoccetti

Khoueiry

et al. 2015

Molecular and Cellular Biology

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The Tet 5-methylcytosine dioxygenases catalyze DNA demethylation by producing 5-hydroxymethylcytosine and further oxidized products. Tet1 and Tet2 are highly expressed in mouse pluripotent cells and downregulated to different extents in somatic cells, but the transcriptional mechanisms are unclear. Here we defined the promoter and enhancer domains in Tet1 and Tet2. Within a 15-kb "superenhancer" of Tet1, there are two transcription start sites (TSSs) with different activation patterns during development. A 6-kb promoter region upstream of the distal TSS is highly active in naive pluripotent cells, autonomously reports Tet1 expression in a transgenic system, and rapidly undergoes DNA methylation and silencing upon differentiation in cultured cells and native epiblast. A second TSS downstream, associated with a constitutively weak CpG-rich promoter, is activated by a neighboring enhancer in naive embryonic stem cells (ESCs) and primed epiblast-like cells (EpiLCs). Tet2 has a CpG island promoter with pluripotency-independent activity and an ESC-specific distal intragenic enhancer; the latter is rapidly downregulated in EpiLCs. Our study reveals distinct modes of transcriptional regulation at Tet1 and Tet2 during cell state transitions of early development. New transgenic reporters using Tet1 and Tet2 cis-regulatory domains may serve to distinguish nuanced changes in pluripotent states and the underlying epigenetic variations.T he study of transcription regulation is fundamental to understand how gene expression and phenotype are regulated during development. ENCODE (encyclopedia of DNA elements) studies recently revealed that the mammalian genome is more complex than previously annotated, in which different transcription start sites (TSSs) often mark core promoters, both intra-and intergenic, to drive the expression of alternative mRNA isoforms (1, 2). Distal elements known as enhancers are often recruitment platforms for cell-type-specific transcription factors and interact with promoter-bound factors to stabilize the association of RNA polymerase II (Pol II) at TSSs (3).Embryonic stem cells (ESCs) derived from the inner cell mass (ICM) of mouse blastocysts represent a unique model of transcription regulation. The widespread presence of "open" chromatin achieved through feed-forward and autoregulatory loops involving transcription factors appears crucial for the transcriptome to adapt rapidly to inductive differentiation signals, allowing the cells to generate all early embryonic lineages (4, 5). This pluripotent state is dependent on the master transcription factors Oct4, Sox2, and Nanog (OSN), which often bind cooperatively at target sites on enhancers. In early mammalian development, the triad of OSN, by binding to different enhancers, orchestrates two states of pluripotency, the "naive" and "primed" conditions resembling the pre-and postimplantation epiblasts, respectively (6, 7). Furthermore, OSN together with Klf4, Esrrb, and Mediator coactivator, all highly expressed in naive ESCs, densely occupy extended d...

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“…Having established the chromatin-state dynamics during in vitro PGC specification, we compared the chromatin states between EpiLCs and epiblast stem cells (EpiSCs) (Factor et al, 2014), which bear robust and little, if any, competence for the germ cell fate, respectively .…”

Section: Epilcs Versus Episcsmentioning

confidence: 99%

Quantitative Dynamics of Chromatin Remodeling during Germ Cell Specification from Mouse Embryonic Stem Cells

et al. 2015

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Germ cell specification is accompanied by epigenetic remodeling, the scale and specificity of which are unclear. Here, we quantitatively delineate chromatin dynamics during induction of mouse embryonic stem cells (ESCs) to epiblast-like cells (EpiLCs) and from there into primordial germ cell-like cells (PGCLCs), revealing large-scale reorganization of chromatin signatures including H3K27me3 and H3K9me2 patterns. EpiLCs contain abundant bivalent gene promoters characterized by low H3K27me3, indicating a state primed for differentiation. PGCLCs initially lose H3K4me3 from many bivalent genes but subsequently regain this mark with concomitant upregulation of H3K27me3, particularly at developmental regulatory genes. PGCLCs progressively lose H3K9me2, including at lamina-associated perinuclear heterochromatin, resulting in changes in nuclear architecture. T recruits H3K27ac to activate BLIMP1 and early mesodermal programs during PGCLC specification, which is followed by BLIMP1-mediated repression of a broad range of targets, possibly through recruitment and spreading of H3K27me3. These findings provide a foundation for reconstructing regulatory networks of the germline epigenome.

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Epigenomic Comparison Reveals Activation of “Seed” Enhancers during Transition from Naive to Primed Pluripotency

Cited by 147 publications

References 45 publications

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Dynamic Switching of Active Promoter and Enhancer Domains Regulates Tet1 and Tet2 Expression during Cell State Transitions between Pluripotency and Differentiation

Quantitative Dynamics of Chromatin Remodeling during Germ Cell Specification from Mouse Embryonic Stem Cells

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