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Id1 maintains embryonic stem cell self-renewal by upregulation of Nanog and repression of Brachyury expression

ABSTRACT: Understanding the mechanism by which embryonic stem (ES) cells self-renew is critical for the realization of their therapeutic potential. Previously it had been shown that in combination with LIF, Id proteins were sufficient to maintain mouse ES cells in a self-renewing state. Here we investigate the requirement for Id1 in maintaing ES cell self-renewal and blocking differentiation. We find that Id1-/- ES cells have a propensity to differentiate and a decreased capacity to self-renew. Chronic or acute loss of Id1 leads to a down-regulation of Nanog, a critical regulator of self-renewal. In addition, in the absence of Id1, ES cells express elevated levels of Brachyury, a marker of mesendoderm differentiation. We find that loss of both Nanog and Id1 is required for the up-regulation of Brachyury, and Id1 maintains Nanog expression by blocking the expression of Zeb1, a repressor of Nanog transcription. These results identify Id1 as an important factor in the maintenance of ES cell self-renewal and suggest a plausible mechanism for its control of lineage commitment. Wild type and Id1-/- ES cells were grown on gelatin under normal self-renewing conditions (in the presence of serum and LIF).

ORGANISM(S): Mus musculus

SUBMITTER: Jeffrey Zhao

PROVIDER: E-GEOD-19144 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Id1 maintains embryonic stem cell self-renewal by upregulation of Nanog and repression of Brachyury expression

Project description:Understanding the mechanism by which embryonic stem (ES) cells self-renew is critical for the realization of their therapeutic potential. Previously it had been shown that in combination with LIF, Id proteins were sufficient to maintain mouse ES cells in a self-renewing state. Here we investigate the requirement for Id1 in maintaing ES cell self-renewal and blocking differentiation. We find that Id1-/- ES cells have a propensity to differentiate and a decreased capacity to self-renew. Chronic or acute loss of Id1 leads to a down-regulation of Nanog, a critical regulator of self-renewal. In addition, in the absence of Id1, ES cells express elevated levels of Brachyury, a marker of mesendoderm differentiation. We find that loss of both Nanog and Id1 is required for the up-regulation of Brachyury, and Id1 maintains Nanog expression by blocking the expression of Zeb1, a repressor of Nanog transcription. These results identify Id1 as an important factor in the maintenance of ES cell self-renewal and suggest a plausible mechanism for its control of lineage commitment.

2011-11-01 | GSE19144 | GEO

ChIP Seq of Oct4, Nanog, H3K27me3 in Oct4+/+ and Oct4 +/- mES cells

Project description:Embryonic stem cell (ESC) pluripotency is governed by a gene regulatory network centred on the transcription factors Oct4 and Nanog. ESCs fluctuate between states of high and low Nanog expression that direct efficient or inefficient self-renewal. To date, robust self-renewing ESC states have only been attained by chemical inhibition of signalling pathways or enforced transgene expression. Here we show that ESCs expressing a reduced range of Oct4 concentrations, typified by Oct4 heterozygous ESCs exhibit stable robust pluripotency. Despite this reduced Oct4 concentration range, this state is characterised by increased genome-wide binding of Oct4, particularly at pluripotency-associated enhancers, homogeneous expression of pluripotency transcription factors, enhanced self-renewal efficiency and delayed differentiation kinetics. In this state, ESCs exhibit increased wnt expression, enhanced LIF-sensitivity, non-responsiveness to FGF signalling and can clonally maintain pluripotency without BMP but remain dependent upon LIF. Robust pluripotency is destabilised either by alteration of the Oct4 level or by removal of LIF. Our findings suggest that robust pluripotency originates from cells with a reduced Oct4 protein concentration and that the wild-type Oct4 range enables effective differentiation.

2013-05-07 | E-MTAB-1617 | biostudies-arrayexpress

Mus musculus

Project description:Id1 maintains embryonic stem cell self-renewal by upregulation of Nanog and repression of Brachyury expression

| PRJNA120693 | ENA

RNAi profiling of mouse embryonic stem cells using short hairpin RNAs against Nanog, Oct4, Sox2, Esrrb, Tbx3, Tcl1, Mm.343880 and Dppa4

Project description:We present an integrated approach to identify genetic mechanisms that control self-renewal in mouse embryonic stem (ES) cells. Short hairpin RNA (shRNA) techniques are employed to down regulate a set of gene-products whose expression patterns suggest self-renewal regulatory functions. We focus on transcriptional regulators and identify seven molecules whose shRNA-mediated depletion induces differentiation, including four whose roles in self-renewal had not been demonstrated. We analyze the expression profiles of embryonic stems (ES) cells transduced with individual shRNA vectors, maintained in the presence of LIF. Experiment Overall Design: We analyze transcriptome dynamics after down-regulating each of the 8 self-renewal regulators identified in the current studies. These are Nanog, Oct4, Sox2, Esrrb, Tbx3, Tcl1, Mm.343880 and Dppa4. Gene specific shRNA transduced GFP+ cells were FACS purified daily during a seven day interval and used to interrogate Affymetrix microarrays. Empty H1P vector served as a reference.

2008-06-13 | E-GEOD-4679 | biostudies-arrayexpress

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation [ChIP-seq]

Project description:Self-renewal of embryonic stem cells (ESCs) cultured in serum-LIF 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 serum-LIF 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 ESRRBhigh 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 ESRRBnegative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.

2018-09-13 | GSE118905 | GEO

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

2018-09-13 | GSE118906 | GEO

Transcription profiling of mouse ES cells overexpressing Akt response to LIF

Project description:Embryonic stem (ES) cells can self-renew indefinitely without losing their differentiation ability to any cell types. Phosphoinositide-3 kinase (PI3K)/Akt signaling plays a pivotal role in various stem cell systems, including the formation of embryonic germ (EG) cells from primordial germ cells and self-renewal of neural stem cells. Here, we show that myristoylated, active form of Akt (myr-Akt) maintained the undifferentiated phenotypes in mouse ES cells without the addition of leukemia inhibitory factor (LIF). The effects of myr-Akt were reversible, because LIF dependence and pluripotent differentiation activity were restored by the deletion of myr-Akt. In addition, myr-Akt-Mer fusion protein, whose enzymatic activity is controlled by 4-hydroxy-tamoxifen, also maintained the pluripotency of not only mouse but also cynomolgus monkey ES cells. These results clearly demonstrate that Akt signaling sufficiently maintains pluripotency in mouse and primate ES cells, and support the notion that PI3K/Akt signaling axis regulates 'stemness' in a broad spectrum of stem cell systems.

2008-06-12 | E-GEOD-2516 | biostudies-arrayexpress

Effect of LIF on ES cells overexpressing Akt

2005-04-12 | GSE2516 | GEO

Function of deubiquitinase USP21 in mouse embryonic stem cell [RNA-Seq]

Project description:Ubiquitination-mediated protein degradation of key transcriptional factors is important to the self-renewal of embryonic stem (ES) cells. However, little is known about the deubiquitination in ES self-renewal and differentiation. Here, we report that deubiquitinase USP21 is an important positive regulator to keep ES cells under undifferentiation stasus by deubiquitination and stabilization of Nanog, a key transcriptional factor of ES cells. Loss of USP21 led to ES cells differentiation and defect in reprogramming.

2016-10-05 | GSE69987 | GEO

Asymmetric self-renewal associated (ASRA) genes

Project description:Cell lines geneticially engineered to undergo conditional asymmetric self-renewal were used to identify genes whose expression is asymmetric self-renewal associated (ASRA). Non-random sister chromatid segregation occurs concordantly with asymmetric self-renewal in these cell lines. Asymmetric self-renewal occurs when murine embryo fibroblasts that are otherwise p53-null are induced to express physiological levels of wildtype p53 protein (Asym). To distinguish p53-responsive genes that also require induction of asymmetric self renewal (i.e., ASRA genes) and/or non-random sister chromatid segregation for change, an additional control cell line, which continues to symmetrically self-renew (with random sister chromatid segregation) even when p53 is induced, was also compared (Symp53). This congenic cell line constitutively expresses the type II inosine monophosphate dehydrogenase (IMPDH II; the rate-limiting enzmye for guanine ribonucleotide biosynthesis) and, thereby, prevents p53-induced asymmetric self-renewal and non-random sister chromatid segregation. Three biological replicates of asymmetrically self-renewing cultures (Asym1-3) were compared with cultures that were symmetrically self-renewing - either because they did not express p53 (3 biological replicates, Sym1-3) or they expressed constitutive IMPDH II (i.e., not regulated by p53) as well as p53 (2 biological replicates, Symp53_1 and 2.)

2010-12-22 | E-GEOD-25334 | biostudies-arrayexpress

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