Nac1 Coordinates a Sub-network of Pluripotency Factors to Regulate Embryonic Stem Cell Differentiation

Malleshaiah, Mohan; Padi, Megha; Rué, Pau; Quackenbush, John; Martínez-Arias, Alfonso; Gunawardena, Jeremy

doi:10.1016/j.celrep.2015.12.101

Cited by 31 publications

(39 citation statements)

References 49 publications

(94 reference statements)

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“…7a, b). The ability of RA to drive ectodermal differentiation seemed unaffected under these conditions, as reported before 25 .…”

Section: Resultssupporting

confidence: 60%

“…Importantly, the two factors we studied in detail, Gbx2 and Tbx3, were previously determined to be part of an essential pluripotency network [51][52][53][54][55] . It has been suggested before that some pluripotency genes are also involved in lineage specification 25,48,49 . Thomson et al showed that Sox2 and Oct4 promote the neuroectodermal and mesendodermal lineage, respectively 48 .…”

Section: Discussionmentioning

confidence: 99%

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Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells

Semrau

Goldmann

Soumillon

et al. 2016

Preprint

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Gene expression heterogeneity in the pluripotent state of mouse embryonic stem cells (mESCs) has been increasingly well-characterized. In contrast, exit from pluripotency and lineage commitment have not been studied systematically at the single-cell level. Here we measure the gene expression dynamics of retinoic acid driven mESC differentiation from pluripotency to lineage commitment, using an unbiased single-cell transcriptomics approach. We find that the exit from pluripotency marks the start of a lineage transition as well as a transient phase of increased susceptibility to lineage specifying signals. Our study reveals several transcriptional signatures of this phase, including a sharp increase of gene expression variability and sequential expression of two classes of transcriptional regulators. In summary, we provide a comprehensive analysis of the exit from pluripotency and lineage commitment at the single cell level, a potential stepping stone to improved lineage manipulation through timing of differentiation cues.

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“…7a, b). The ability of RA to drive ectodermal differentiation seemed unaffected under these conditions, as reported before 25 .…”

Section: Resultssupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells

Semrau

Goldmann

Soumillon

et al. 2016

Preprint

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“…NAC1 has been reported to have a role in regulating the stemness and differentiation of stem cells through its interaction with the factors like Nanog, Oct4, Tcf3 and Sox2. 6 , 37 , 38 As altered energy metabolism can impact fate of stem cells, 39 the NAC1-promoted glycolysis may contribute to its role in regulating differentiation of stem cells.…”

Section: Discussionmentioning

confidence: 99%

Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis

et al. 2017

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Nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB/POZ gene family, has emerging roles in cancer. In this study, we identified the NAC1-HDAC4-HIF-1α axis as an important pathway in regulating glycolysis and hypoxic adaptation in tumor cells. We show that nuclear NAC1 binds to histone deacetylase type 4 (HDAC4), hindering phosphorylation of HDAC4 at Ser246 and preventing its nuclear export that leads to cytoplasmic degradation of the deacetylase. Accumulation of HDAC4 in the nuclei results in an attenuation of HIF-1α acetylation, enhancing the stabilization and transcriptional activity of HIF-1α and strengthening adaptive response of cells to hypoxia. We also show the role of NAC1 in promoting glycolysis in a mouse xenograft model, and demonstrate that knockdown of NAC1 expression can reinforce the antitumor efficacy of bevacizumab, an inhibitor of angiogenesis. Clinical implication of the NAC1-HDAC4-HIF-1α pathway is suggested by the results showing that expression levels of these proteins are significantly correlative in human tumor specimens and associated with the disease progression. This study not only reveals an important function of NAC1 in regulating glycolysis, but also identifies the NAC1-HDAC4-HIF-1α axis as a novel molecular pathway that promotes survival of hypoxic tumor cells.

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“…Recently, Nac1 was reported to be needed for ME differentiation of ESCs. Nac1 KD resulted in a significant reduction of the ME fate, but induced the NE fate choice [ 33 ]. However, our study indicates that Nac1 KD facilitates the ME differentiation of ESCs.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that Nac1 knockdown (KD) induces ESC differentiation [ 31 ], whereas Nac1 knockout does not induce embryonic lethality or result in grossly noticeable morphological phenotypes in mice [ 32 ]. Following the use of integrative methodologies, Nac1 has been suggested to act as a lineage specifier that mediates mesendoderm (ME) and neuroectoderm (NE) cell fate selection [ 33 ]. However, the precise functions and mechanisms underlying the role of Nac1 in the regulation of ESC self-renewal and pluripotency are not well defined.…”

Section: Introductionmentioning

confidence: 99%

Nac1 promotes self-renewal of embryonic stem cells through direct transcriptional regulation of c-Myc

Ruan

et al. 2017

Oncotarget

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The pluripotency transcriptional network in embryonic stem cells (ESCs) is composed of distinct functional units including the core and Myc units. It is hoped that dissection of the cellular functions and interconnections of network factors will aid our understanding of ESC and cancer biology. Proteomic and genomic approaches have identified Nac1 as a member of the core pluripotency network. However, previous studies have predominantly focused on the role of Nac1 in psychomotor stimulant response and cancer pathogenesis. In this study, we report that Nac1 is a self-renewal promoting factor, but is not required for maintaining pluripotency of ESCs. Loss of function of Nac1 in ESCs results in a reduced proliferation rate and an enhanced differentiation propensity. Nac1 overexpression promotes ESC proliferation and delays ESC differentiation in the absence of leukemia inhibitory factor (LIF). Furthermore, we demonstrated that Nac1 directly binds to the c-Myc promoter and regulates c-Myc transcription. The study also revealed that the function of Nac1 in promoting ESC self-renewal appears to be partially mediated by c-Myc. These findings establish a functional link between the core and c-Myc-centered networks and provide new insights into mechanisms of stemness regulation in ESCs and cancer.

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Nac1 Coordinates a Sub-network of Pluripotency Factors to Regulate Embryonic Stem Cell Differentiation

Cited by 31 publications

References 49 publications

Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells

Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells

Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis

Nac1 promotes self-renewal of embryonic stem cells through direct transcriptional regulation of c-Myc

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