Eed/Sox2 regulatory loop controls ES cell self-renewal through histone methylation and acetylation

Ura, Hiroki; Murakami, Kazuhiro; Akagi, Tadayuki; Kinoshita, Keiji; Yamaguchi, Satoshi; Masui, Shinji; Niwa, Hitoshi; Koide, Hiroshi; Yokota, Takashi

doi:10.1038/emboj.2011.126

Cited by 29 publications

(24 citation statements)

References 51 publications

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“…PCR products were cloned into pGL4.10 and termed pGL4.10-Dax1P 546 bp-mutERRE1, -mutERRE2, or -mutERRE1&2. To construct reporter plasmids of Oct3/4-responsive elements of the Esrrb gene, approximately 500-bp sequences, including either the first Oct3/4-binding site (ϩ8924 to ϩ8931) or the second Oct3/4-binding site (ϩ34733 to ϩ34740), were amplified by PCR and cloned into the pGL4 promoter (26), and we termed these plasmids pGL4P-Oct3/4#A and pGL4P-Oct3/4#B. To construct the Oct3/4-binding site mutated pGL4P-Oct3/4#A plasmid, the mutated Oct3/4-binding element was constructed by PCR using specific primers.…”

Section: Methodsmentioning

confidence: 99%

Dax1 Associates with Esrrb and Regulates Its Function in Embryonic Stem Cells

Uranishi

Akagi

Sun

et al. 2013

Molecular and Cellular Biology

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Self-renewal capacity and pluripotency, which are controlled by the Oct3/4-centered transcriptional regulatory network, are major characteristics of embryonic stem (ES) cells. Nuclear hormone receptor Dax1 is one of the crucial factors in the network. Here, we identified an orphan nuclear receptor, Esrrb (estrogen-related receptor beta), as a Dax1-interacting protein. Interaction of Dax1 and Esrrb was mediated through LXXLL motifs of Dax1 and the activation-and ligand-binding domains of Esrrb. Furthermore, Esrrb enhanced the promoter activity of the Dax1 gene via direct binding to Esrrb-binding site 1 (ERRE1, where "ERRE" represents "Esrrb-responsive element") of the promoter. Expression of Dax1 was suppressed followed by Oct3/4 repression; however, overexpression of Esrrb maintained expression of Dax1 even in the absence of Oct3/4, indicating that Dax1 is a direct downstream target of Esrrb and that Esrrb can regulate Dax1 expression in an Oct3/4-independent manner. We also found that the transcriptional activity of Esrrb was repressed by Dax1. Furthermore, we revealed that Oct3/4, Dax1, and Esrrb have a competitive inhibition capacity for each complex. These data, together with previous findings, suggest that Dax1 functions as a negative regulator of Esrrb and Oct3/4, and these molecules form a regulatory loop for controlling the pluripotency and self-renewal capacity of ES cells. P luripotency and self-renewal capacity are major characteristics of murine embryonic stem (ES) cells. Leukemia inhibitory factor (LIF) plays an important role for the self-renewal of ES cells, and depletion of LIF from ES cell culture medium leads to spontaneous differentiation of cells and results in a failure of self-renewal (1, 2). A large number of transcription factors function downstream of signaling by LIF, and several transcription factors, including STAT3, Oct3/4, Sox2, and Nanog, play crucial roles for pluripotency and self-renewal of ES cells (3-5). Artificial activation of STAT3, which is achieved by 4-hydroxytamoxifen stimulation of nuclear localization of the STAT3-estrogen receptor fusion protein (STAT3ER), as well as forced expression of Nanog, accelerates the self-renewal in a LIF-independent manner (6-8). Oct3/4-deficient embryos develop to the blastocyst stage, but their inner cell mass (ICM), from which ES cells are established, loses pluripotency, and the deletion of Oct3/4 expression in ES cells promotes differentiation into extraembryonic trophectodermal cells (9, 10). Sox2-deficient blastocysts form abnormal ICM and fail to achieve outgrowth (11). ES cells lacking the Sox2 gene differentiate into trophoblast cells (12).Actually, these transcription factors collaboratively regulate gene expression with other factors and contribute to maintenance of pluripotency and self-renewal of ES cells. For instance, Oct3/4 interacts with Sox2, and this complex enhances expression of ES cell-specific genes, including Fgf4, Lefty1, Nanog, UTF1, and Sox2 (13). ␤-Catenin is also a binding partner of Oct3/4, and the complex re...

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Section: Methodsmentioning

confidence: 99%

Dax1 Associates with Esrrb and Regulates Its Function in Embryonic Stem Cells

Uranishi

Akagi

Sun

et al. 2013

Molecular and Cellular Biology

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“…Also identified were the nuclear receptor Esrrb, T-box transcription factor-3 (Tbx3), and T-cell leukemia oncogene 1 (Tcl1). Esrrb has subsequently been found to interact with Oct4 and Nanog (van den Berg et al 2008;Zhang et al 2008) and to act as a reprogramming factor (Feng et al 2009). However, during development Esrrb is required in the placenta, not in the embryo (Luo et al 1997), suggesting that its function in pluripotent cells can be substituted by an alternative pathway.…”

Section: A Transcription Factor Network That Sustains Naïve Pluripotencymentioning

confidence: 99%

Pluripotency in the Embryo and in Culture

Nichols

Smith

2012

Cold Spring Harbor Perspectives in Biology

272

254

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SUMMARYSpecific cells within the early mammalian embryo have the capacity to generate all somatic lineages plus the germline. This property of pluripotency is confined to the epiblast, a transient tissue that persists for only a few days. In vitro, however, pluripotency can be maintained indefinitely through derivation of stem cell lines. Pluripotent stem cells established from the newly formed epiblast are known as embryonic stem cells (ESCs), whereas those generated from later stages are called postimplantation epiblast stem cells (EpiSCs). These different classes of pluripotent stem cell have distinct culture requirements and gene expression programs, likely reflecting the dynamic development of the epiblast in the embryo. In this chapter we review current understanding of how the epiblast forms and relate this to the properties of derivative stem cells. We discuss whether ESCs and EpiSCs are true counterparts of different phases of epiblast development or are culture-generated phenomena. We also consider the proposition that early epiblast cells and ESCs may represent a naïve ground state without any prespecification of lineage choice, whereas later epiblasts and EpiSCs may be primed in favor of particular fates.

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“…However, this appears to be accomplished either by direct complementation of Ezh2 enzymatic activity by Ezh1 (38) or by compensatory regulations that overcome PRC2 function in maintaining ES cells undifferentiated. In fact, Suz12 and Eed mutants ES cells have been shown to express higher levels of several ESCspecific genes, including Nanog, Oct 3/4, and Sox2, which could maintain the cells in the undifferentiated state trough a network of gene regulatory circuits (38,45,47).…”

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confidence: 99%