Nodal Signaling Recruits the Histone Demethylase Jmjd3 to Counteract Polycomb-Mediated Repression at Target Genes

Dahle, Øyvind; Kumar, Amit; Kuehn, Michael R.

doi:10.1126/scisignal.2000841

Cited by 109 publications

(119 citation statements)

References 46 publications

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“…This mark is often found in conjunction with H3K4me3, and, as a result, these regions of chromatin are referred to as bivalent domains and thought to reflect an inactive yet poised/ primed state (Voigt et al 2013). In ChIP-seq studies in hESCs and mESCs, NODAL/activin induction of specific genes, such as Nodal itself and the mesendodermal genes Eomes and Gsc, has been shown to be associated with loss of H3K27me3 (Dahle et al 2010;Kim et al 2011). Demethylation of H3K27me3 in response to activin/NODAL has been thought to be mediated by the enzyme JMJD3 ( jumonji domain containing 3), as SMAD2/3 can bind JMJD3 in immunoprecipitations, and JMJD3 is recruited on activin signaling to the SMAD2/3-binding sites in the regulatory regions of the Gsc and Eomes genes .…”

Section: Smad Interactions With Coactivators and Corepressors Lead Tomentioning

confidence: 99%

Transcriptional Control by the SMADs

Hill

2016

Cold Spring Harb Perspect Biol

282

256

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The transforming growth factor-b (TGF-b) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-b family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.

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Section: Smad Interactions With Coactivators and Corepressors Lead Tomentioning

confidence: 99%

Transcriptional Control by the SMADs

Hill

2016

Cold Spring Harb Perspect Biol

282

256

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“…HBE is the only active Nodal enhancer in ESCs, while it is ASE that is the most active one in EpiSCs [23,92]. Both enhancers are dependent on Activin/Nodal signalling, but their activation relies on pSmad2/3 interacting with distinct transcription factors: the pluripotency factor Oct4 in the case of HBE (figure 3) [8,93], and FoxH1 in that of ASE [94]. Deletion of HBE in ESCs eliminates Nodal expression, confirming that HBE is essential to the expression of the gene in these cells.…”

Section: Embryonic Stem Cells As a Model To Study Early Function And mentioning

confidence: 99%

Activin/Nodal signalling before implantation: setting the stage for embryo patterning

Papanayotou

Collignon

2014

Phil. Trans. R. Soc. B

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Activins and Nodal are members of the transforming growth factor beta (TGF-b) family of growth factors. Their Smad2/3-dependent signalling pathway is well known for its implication in the patterning of the embryo after implantation. Although this pathway is active early on at preimplantation stages, embryonic phenotypes for loss-of-function mutations of prominent components of the pathway are not detected before implantation. It is only fairly recently that an understanding of the role of the Activin/Nodal signalling pathway at these stages has started to emerge, notably from studies detailing how it controls the expression of target genes in embryonic stem cells. We review here what is currently known of the TGF-b-related ligands that determine the activity of Activin/Nodal signalling at preimplantation stages, and recent advances in the elucidation of the Smad2/3-dependent mechanisms underlying developmental progression.

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“…JMJD3 is expressed predominantly in stem cells and is involved in differentiation and dedifferentiation processes including neural and epidermal differentiation, skin repair, and inflammation (11). In mouse embryonic stem cells, JMJD3 participates in the Nodal and Brachyury pathways, both of which are critical during vertebrate development (34).…”

mentioning

confidence: 99%

Jumonji domain-containing protein 3 regulates histone 3 lysine 27 methylation during bovine preimplantation development

Cánovas

Cibelli

Ross

2012

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the mechanisms of epigenetic remodeling that follow fertilization is a fundamental step toward understanding the bases of early embryonic development and pluripotency. Extensive and dynamic chromatin remodeling is observed after fertilization, including DNA methylation and histone modifications. These changes underlie the transition from gametic to embryonic chromatin and are thought to facilitate embryonic genome activation. In particular, trimethylation of histone 3 lysine 27 (H3K27me3) is associated with gene-specific transcription repression. Global levels of this epigenetic mark are high in oocyte chromatin and decrease to minimal levels at the time of embryonic genome activation. We provide evidence that the decrease in H3K27me3 observed during early development is cell-cycle independent, suggesting an active mechanism for removal of this epigenetic mark. Among H3K27me3-specific demethylases, Jumonji domain-containing protein 3 (JMJD3), but not ubiquitously transcribed tetratricopeptide repeat X (UTX), present high transcript levels in oocytes. Soon after fertilization JMJD3 protein levels increase, concurrent with a decrease in mRNA levels. This pattern of expression suggests maternal inheritance of JMJD3. Knockdown of JMJD3 by siRNA injection in parthenogenetically activated metaphase II oocytes resulted in inhibition of the H3K27me3 decrease normally observed in preimplantation embryos. Moreover, knockdown of JMJD3 in oocytes reduced the rate of blastocyst development. Overall, these results indicate that JMJD3 is involved in active demethylation of H3K27me3 during early embryo development and that this mark plays an important role during the progression of embryos to blastocysts.G amete nuclei undergo extensive chromatin remodeling soon after fertilization, including alterations to DNA methylation levels and posttranslational histone tail modification. These changes are known to influence chromatin structure and transcriptional readout (1) and also to promote embryonic genome activation (EGA) (2), which occurs in humans and cows after three to four cell divisions (3-5). Because the first few cell divisions occur without embryonic gene transcription, maternally inherited mRNA and proteins present in the oocyte are likely responsible for inducing these epigenetic changes (6).Histone lysine methylation is involved in transcriptional repression and/or activation and plays a key role during lineage specification and cell differentiation (7). Di-and trimethylation of histone 3 lysine 27 (H3K27) are catalyzed by the polycomb repressive complex 2 (PRC2), which has three essential components: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 (SUZ12) (8-10). These epigenetic marks are specifically associated with gene repression (11) and are typical of many key developmental genes in embryonic stem cells, stem cell maintenance (12-14), and regulation of pluripotency (15). In mouse embryos, asymmetric distribution of trimethylated H3K27 (H3K27me3) i...

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Nodal Signaling Recruits the Histone Demethylase Jmjd3 to Counteract Polycomb-Mediated Repression at Target Genes

Cited by 109 publications

References 46 publications

Transcriptional Control by the SMADs

Transcriptional Control by the SMADs

Activin/Nodal signalling before implantation: setting the stage for embryo patterning

Jumonji domain-containing protein 3 regulates histone 3 lysine 27 methylation during bovine preimplantation development

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