Generation of mouse ES cell lines engineered for the forced induction of transcription factors

Correa-Cerro, Lina S.; Piao, Yulan; Sharov, Alexei A.; Nishiyama, Akira; Cadet, Jean Scotty; Yu, Hong; Sharova, Lioudmila V.; Li, Xin; Hoang, Hien G.; Thomas, Matthew; Qian, Yong; Dudekula, Dawood B.; Meyers, Emily; Binder, Bernard Y. K.; Mowrer, Gregory; Bassey, Uwem C.; Longo, Dan L.; Schlessinger, David; Ko, Minoru S.H.

doi:10.1038/srep00167

Cited by 48 publications

(79 citation statements)

References 21 publications

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“…This engineered ESC line was originally generated by Dr Minoru Ko at the National Institute of Aging (Correa-Cerro et al, 2011). Cells were grown on a feeder layer of mitomycin-treated puromycinresistant mouse embryonic fibroblasts (MEFs) in standard ESC medium, Fig.…”

Section: Tfap2c-inducible Esc and Tsc Culturementioning

confidence: 99%

Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage

et al. 2015

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Cell fate decisions are fundamental to the development of multicellular organisms. In mammals the first cell fate decision involves segregation of the pluripotent inner cell mass and the trophectoderm, a process regulated by cell polarity proteins, HIPPO signaling and lineagespecific transcription factors such as CDX2. However, the regulatory mechanisms that operate upstream to specify the trophectoderm lineage have not been established. Here we report that transcription factor AP-2γ (TFAP2C) functions as a novel upstream regulator of Cdx2 expression and position-dependent HIPPO signaling in mice. Loss-and gain-of-function studies and promoter analysis revealed that TFAP2C binding to an intronic enhancer is required for activation of Cdx2 expression during early development. During the 8-cell to morula transition TFAP2C potentiates cell polarity to suppress HIPPO signaling in the outside blastomeres. TFAP2C depletion triggered downregulation of PARD6B, loss of apical cell polarity, disorganization of F-actin, and activation of HIPPO signaling in the outside blastomeres. Rescue experiments using Pard6b mRNA restored cell polarity but only partially corrected position-dependent HIPPO signaling, suggesting that TFAP2C negatively regulates HIPPO signaling via multiple pathways. Several genes involved in regulation of the actin cytoskeleton (including Rock1, Rock2) were downregulated in TFAP2C-depleted embryos. Inhibition of ROCK1 and ROCK2 activity during the 8-cell to morula transition phenocopied TFAP2C knockdown, triggering a loss of position-dependent HIPPO signaling and decrease in Cdx2 expression. Altogether, these results demonstrate that TFAP2C facilitates trophectoderm lineage specification by functioning as a key regulator of Cdx2 transcription, cell polarity and position-dependent HIPPO signaling.

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Section: Tfap2c-inducible Esc and Tsc Culturementioning

confidence: 99%

Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage

et al. 2015

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“…1A-C) (Nishiyama et al, 2009;Correa-Cerro et al, 2011). From a list of 137 TFs sorted by the magnitude of transcriptome perturbation, we arbitrarily selected the top 36 TFs (Fig.…”

Section: Identification Of Tfs That Direct Mouse Esc Differentiation mentioning

confidence: 99%

“…We have measured the global gene expression profiles (i.e. transcriptome) of these ESC lines 48 h after overexpressing each TF (Correa-Cerro et al, 2011;Nishiyama et al, 2009). By comparing these transcriptome data to the publicly available expression profiles of a variety of cell types (Su et al, 2002;Wu et al, 2009), we generated a correlation matrix that can help to predict the TF-induced direction of ESC differentiation (Correa-Cerro et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…The identity of cells can be altered by the forced induction of combination of transcription factors (TFs) (Takahashi and Yamanaka, 2006;Vierbuchen et al, 2010;Ieda et al, 2010;Sekiya and Suzuki, 2011;Huang et al, 2011;Hiramatsu et al, 2011), the forced induction of single TFs (Davis et al, 1987;Nishiyama et al, 2009;Correa-Cerro et al, 2011;Yamamizu et al, 2013) or by the repression of single TFs (Skarnes et al, 2004;Ivanova et al, 2006;Collins et al, 2007;Nishiyama et al, 2013). As an aid to analyze the effects of TF manipulation on mouse embryonic stem cell (ESC) differentiation, we have established the NIA Mouse ESC Bank (Nishiyama et al, 2009;Correa-Cerro et al, 2011), in which each of 137 TFs, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…As an aid to analyze the effects of TF manipulation on mouse embryonic stem cell (ESC) differentiation, we have established the NIA Mouse ESC Bank (Nishiyama et al, 2009;Correa-Cerro et al, 2011), in which each of 137 TFs, i.e. 7-10% of all TFs encoded in the mouse genome (Kanamori et al, 2004), can be induced in a tetracycline-regulatable manner.…”

Section: Introductionmentioning

confidence: 99%

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SOX9 accelerates ESC differentiation to three germ layer lineages by repressing SOX2 expression through P21 (WAF1/CIP1)

Yamamizu

Schlessinger

2014

Development

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Upon removal of culture conditions that maintain an undifferentiated state, mouse embryonic stem cells (ESCs) differentiate into various cell types. Differentiation can be facilitated by forced expression of certain transcription factors (TFs), each of which can generally specify a particular developmental lineage. We previously established 137 mouse ESC lines, each of which carried a doxycycline-controllable TF. Among them, Sox9 has unique capacity: its forced expression accelerates differentiation of mouse ESCs into cells of all three germ layers. With the additional use of specific culture conditions, overexpression of Sox9 facilitated the generation of endothelial cells, hepatocytes and neurons from ESCs. Furthermore, Sox9 action increases formation of p21 (WAF1/CIP1), which then binds to the SRR2 enhancer of pluripotency marker Sox2 and inhibits its expression. Knockdown of p21 abolishes inhibition of Sox2 and Sox9-accelerated differentiation, and reduction of Sox2 2 days after the beginning of ESC differentiation can comparably accelerate mouse ESC formation of cells of three germ layers. These data implicate the involvement of the p21-Sox2 pathway in the mechanism of accelerated ESC differentiation by Sox9 overexpression. The molecular cascade could be among the first steps to program ESC differentiation.

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FOXC1 negatively regulates BMP‐SMAD activity and Id1 expression during osteoblast differentiation

Caddy

Luoma

Berry

2020

J of Cellular Biochemistry

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Bone morphogenetic proteins regulate a diverse range of biological processes through their activation of SMAD1, SMAD5, or SMAD8 proteins that, in turn, regulate gene expression. These SMAD transcription factors achieve a layer of functional specificity in different cell types largely through actions with additional transcriptional regulatory molecules. In this study, we demonstrate that the forkhead box C1 (FOXC1) transcription factor can modulate bone morphogenetic protein (BMP) signaling to impair the expression of BMP4responsive genes and prevent the efficient osteoblast differentiation. We demonstrate that repression occurs downstream of BMP signaling and impacts the ability SMAD1 or SMAD5 to activate gene expression. Repression of SMAD activity requires FOXC1 DNA-binding capacity and the transcriptional inhibitory domain of FOXC1. We report that FOXC1 inhibits BMP4 induction of Id1 expression and identify a motif in the regulatory region of mouse Id1 gene that FOXC1 binds. We determine that this inhibition by FOXC1 binding does not affect SMAD1, SMAD5, or SMAD8 binding to its target sequence in the Id1 gene. Finally, we determine that the elevated expression of FOXC1 can reduces expression osteogenic differentiation genes in mouse embryonic stems directed to the osteoblast lineage through BMP4 treatment. Together, these findings indicate that FOXC1 can negatively regulate certain aspects of BMP4 signaling required for osteoblast differentiation. We propose that FOXC1 acts to attenuate the initial BMP-activated pathways that establish osteoblast differentiation and allow for terminal osteoblast differentiation to conclude. K E Y W O R D Sbone morphogenetic proteins, differentiation, forkhead box, osteoblast, transcription factor

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Generation of mouse ES cell lines engineered for the forced induction of transcription factors

Cited by 48 publications

References 21 publications

Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage

Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage

SOX9 accelerates ESC differentiation to three germ layer lineages by repressing SOX2 expression through P21 (WAF1/CIP1)

FOXC1 negatively regulates BMP‐SMAD activity and Id1 expression during osteoblast differentiation

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