β-Catenin Fluctuates in Mouse ESCs and Is Essential for Nanog-Mediated Reprogramming of Somatic Cells to Pluripotency

Marucci, Lucia; Pedone, Elisa; Vicino, Umberto Di; Sanuy-Escribano, Blanca; Isalan, Mark; Cosma, María Pía

doi:10.1016/j.celrep.2014.08.011

Cited by 49 publications

(57 citation statements)

References 48 publications

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“…Alternatively, it is now possible to target genomes directly with site-directed nucleases, such as CRISPR-Cas976. Using such technology, it is possible to integrate synthetic open reading frames just downstream of the transcription start site; this allows one to capture endogenous gene regulatory functions in their full promoter-enhancer contexts77. One limitation for this technology is the availability of PAM sites and the accessibility of Cas9 nuclease to chromatin787980.…”

Section: Discussionmentioning

confidence: 99%

Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis

Senthivel

Sturrock

Piedrafita

et al. 2016

Sci Rep

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Nonlinear responses to signals are widespread natural phenomena that affect various cellular processes. Nonlinearity can be a desirable characteristic for engineering living organisms because it can lead to more switch-like responses, similar to those underlying the wiring in electronics. Steeper functions are described as ultrasensitive, and can be applied in synthetic biology by using various techniques including receptor decoys, multiple co-operative binding sites, and sequential positive feedbacks. Here, we explore the inherent non-linearity of a biological signaling system to identify functions that can potentially be exploited using cell genome engineering. For this, we performed genome-wide transcription profiling to identify genes with ultrasensitive response functions to Hepatocyte Growth Factor (HGF). We identified 3,527 genes that react to increasing concentrations of HGF, in Madin-Darby canine kidney (MDCK) cells, grown as cysts in 3D collagen cell culture. By fitting a generic Hill function to the dose-responses of these genes we obtained a measure of the ultrasensitivity of HGF-responsive genes, identifying a subset with higher apparent Hill coefficients (e.g. MMP1, TIMP1, SNORD75, SNORD86 and ERRFI1). The regulatory regions of these genes are potential candidates for future engineering of synthetic mammalian gene circuits requiring nonlinear responses to HGF signalling.

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Section: Discussionmentioning

confidence: 99%

Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis

Senthivel

Sturrock

Piedrafita

et al. 2016

Sci Rep

Self Cite

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“…WNT activation was previously shown to be not only rate limiting for naïve reversion of mEpiSCs, but also facilitated mESC derivation from 'nonpermissive' mouse strains (Faunes et al, 2013). Additionally, both nuclear (transcriptional) and cytoplasmic (non-transcriptional) activities of β-catenin have been linked to stabilizing mouse naïve pluripotency via interactions with E-cadherin and cytoplasmic OCT4 and NANOG (Marucci et al, 2014). Furthermore, although 2i sufficiently stabilized naïve reversion of mEpiSCs, some mouse strains required reinforcement of KLF4, c-MYC or β-catenin activities (Hanna et al, 2010;Ye et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality

et al. 2016

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The derivation and maintenance of human pluripotent stem cells (hPSCs) in stable naïve pluripotent states has a wide impact in human developmental biology. However, hPSCs are unstable in classical naïve mouse embryonic stem cell (ESC) WNT and MEK/ERK signal inhibition (2i) culture. We show that a broad repertoire of conventional hESC and transgene-independent human induced pluripotent stem cell (hiPSC) lines could be reverted to stable human preimplantation inner cell mass (ICM)-like naïve states with only WNT, MEK/ERK, and tankyrase inhibition (LIF-3i). LIF-3i-reverted hPSCs retained normal karyotypes and genomic imprints, and attained defining mouse ESC-like functional features, including high clonal self-renewal, independence from MEK/ERK signaling, dependence on JAK/ STAT3 and BMP4 signaling, and naïve-specific transcriptional and epigenetic configurations. Tankyrase inhibition promoted a stable acquisition of a human preimplantation ICM-like ground state via modulation of WNT signaling, and was most efficacious in efficiently reprogrammed conventional hiPSCs. Importantly, naïve reversion of a broad repertoire of conventional hiPSCs reduced lineage-primed gene expression and significantly improved their multilineage differentiation capacities. Stable naïve hPSCs with reduced genetic variability and improved functional pluripotency will have great utility in regenerative medicine and human disease modeling.

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“…Such genes, we suggest, belong to the epigenetic mediator category and include, for example, well-known pluripotency factors such as NANOG 66 , OCT4 (also known as POU5F1 ) 67 and WNT signalling members 68 . Epigenetically altered genes in induced pluripotent stem cells largely overlap epigenetically altered genes in cancer 69 .…”

Section: Epigenetic Mediatorsmentioning

confidence: 99%

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

2016

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This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of ‘tumour progenitor genes’. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: ‘epigenetic mediators’, corresponding to the tumour progenitor genes suggested earlier; ‘epigenetic modifiers’ of the mediators, which are frequently mutated in cancer; and ‘epigenetic modulators’ upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.

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β-Catenin Fluctuates in Mouse ESCs and Is Essential for Nanog-Mediated Reprogramming of Somatic Cells to Pluripotency

Cited by 49 publications

References 48 publications

Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis

Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis

Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

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