The SMAD2/3 corepressor SNON maintains pluripotency through selective repression of mesendodermal genes in human ES cells

Tsuneyoshi, Norihiro; Tan, Ee Kim; Sadasivam, Akila; Poobalan, Yogavalli; Sumi, Tomonori; Nakatsuji, Norio; Suemori, Hirofumi; Dunn, N. Ray

doi:10.1101/gad.201772.112

Cited by 28 publications

(24 citation statements)

References 33 publications

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“…This agrees with the important role of Pou5f1 in primed mES cells (B4) and EpiLCs (N2) and the need to downregulate Pou5f1 to induce neural differentiation (N4). This is in accordance with their declining mRNA levels at N4, which is necessary to commit to differentiation . Other genes like Zeb2 have roughly an equal number of consistent and inconsistent interactions, suggesting that Zeb2 protein (and possibly mRNA) levels are important to steer cells into one specific lineage and suppress other lineages, and also promote cell maturation, which is in line with Zeb2 ‐knockout studies in nervous systems in vivo and ES cells .…”

Section: Resultssupporting

confidence: 78%

Integrative and perturbation-based analysis of the transcriptional dynamics of TGFβ/BMP system components in transition from embryonic stem cells to neural progenitors

et al. 2019

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Cooperative actions of extrinsic signals and cell-intrinsic transcription factors alter gene regulatory networks enabling cells to respond appropriately to environmental cues. Signaling by transforming growth factor type β (TGFβ) family ligands (eg, bone morphogenetic proteins [BMPs] and Activin/Nodal) exerts cell-type specific and context-dependent transcriptional changes, thereby steering cellular transitions throughout embryogenesis. Little is known about coordinated regulation and transcriptional interplay of the TGFβ system. To understand intrafamily transcriptional regulation as part of this system's actions during development, we selected 95 of its components and investigated their mRNA-expression dynamics, gene-gene interactions, and single-cell expression heterogeneity in mouse embryonic stem cells transiting to neural progenitors. Interrogation at 24 hour intervals identified four types of temporal gene transcription profiles that capture all stages, that is, pluripotency, epiblast formation, and neural commitment. Then, between each stage we performed esiRNA-based perturbation of each individual component and documented the effect on steady-state mRNA levels of the remaining 94 components. This exposed an intricate system of multilevel regulation whereby the majority of gene-gene interactions display a marked cell-stage specific behavior. Furthermore, single-cell RNA-profiling at individual stages demonstrated the presence of detailed co-expression modules and subpopulations showing stable co-expression modules such as that of the core pluripotency genes at all stages. Our combinatorial experimental approach demonstrates how intrinsically complex transcriptional regulation within a given pathway is during cell fate/state transitions. cell state transitions, embryonic stem cells, esiRNA, genetic interaction, neural differentiation, signaling pathway, TGFβ/BMP 204 DRIES ET AL.

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Section: Resultssupporting

confidence: 78%

Integrative and perturbation-based analysis of the transcriptional dynamics of TGFβ/BMP system components in transition from embryonic stem cells to neural progenitors

et al. 2019

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“…Culturing ESCs in the absence of LIF on low-attachment plates formed embryoid bodies. Human ESCs were cultured and differentiated to the endoderm lineage as described [11]. D,L-alpha-difluoromethylornithine (DFMO) (Cayman Chemicals) and Putrescine (Sigma) were used at 1 mM concentration for all experiments.…”

Section: Cell Culturementioning

confidence: 99%

MINDY1 Is a Downstream Target of the Polyamines and Promotes Embryonic Stem Cell Self-Renewal

et al. 2018

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Embryonic stem cells have the ability to self-renew or differentiate and these processes are under tight control. We previously reported that the polyamine regulator AMD1 is critical for embryonic stem cell self-renewal. The polyamines putrescine, spermidine, and spermine are essential organic cations that play a role in a wide array of cellular processes. Here, we explore the essential role of the polyamines in the promotion of self-renewal and identify a new stem cell regulator that acts downstream of the polyamines: MINDY1. MINDY1 protein levels are high in embryonic stem cells (ESCs) and are dependent on high polyamine levels. Overexpression of MINDY1 can promote ESC self-renewal in the absence of the usually essential cytokine Leukemia Inhibitory Factor (LIF). MINDY1 protein is prenylated and this modification is required for its ability to promote self-renewal. We go on to show that Mindy1 RNA is targeted for repression by mir-710 during Neural Precursor cell differentiation. Taken together, these data demonstrate that high polyamine levels are required for ESC self-renewal and that they function, in part, through promotion of high MINDY1 levels. STEM CELLS 2018; 00:000-000 SIGNIFICANCE STATEMENTThis article shows that the polyamines, putrescine, spermidine, and spermine are essential for the maintenance of embryonic stem cell self-renewal. Inhibition of polyamine synthesis causes differentiation. This study identifies the MINDY1 protein as being a critical downstream target of the polyamines in driving self-renewal. MINDY1 functions to remove ubiquitin from target proteins this preventing their degradation. This study proposes that MINDY1 is a new critical regulator of stem cell self-renewal that functions to promote the stability of core self-renewal proteins.

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“…This may be relevant at longer times after ligand induction, because in most cell types SKI and SKIL are degraded within 30 min of TGF-b/NODAL/activin stimulation, and levels of SKIL in particular recover quickly as they are induced in response to ligand (Stroschein et al 1999;Levy et al 2007;Le Scolan et al 2008). SKIL binding with activated SMAD2/3-containing complexes has been proposed to explain repression of mesendodermal genes in human ESCs (Tsuneyoshi et al 2012). …”

Section: Transcription Factors Interacting With Smad1/5mentioning

confidence: 99%

Transcriptional Control by the SMADs

Hill

2016

Cold Spring Harb Perspect Biol

289

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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The SMAD2/3 corepressor SNON maintains pluripotency through selective repression of mesendodermal genes in human ES cells

Cited by 28 publications

References 33 publications

Integrative and perturbation-based analysis of the transcriptional dynamics of TGFβ/BMP system components in transition from embryonic stem cells to neural progenitors

Integrative and perturbation-based analysis of the transcriptional dynamics of TGFβ/BMP system components in transition from embryonic stem cells to neural progenitors

MINDY1 Is a Downstream Target of the Polyamines and Promotes Embryonic Stem Cell Self-Renewal

Transcriptional Control by the SMADs

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