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Effect of Foxd1 knockdown in the reprogramming process

ABSTRACT: It remains unclear how the ectopic expression of defined transcription factors induces dynamic changes in gene expression profiles that establish a pluripotent state during direct cell reprogramming. In the present study, we first identified a temporal gene expression program during the reprogramming process. Promoter analyses then predicted the role of two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of the gene expression program. Knockdown of Foxd1 or Foxo1 reduced the number of induced pluripotent stem cells (iPSCs). The knockout of Foxd1 prevented the downstream transcription program, including the expression of reprogramming marker genes. Interestingly, the expression level of Foxd1 was also transiently increased in a small population of cells in the middle stage of reprogramming. The presence or absence of Foxd1 expression in this stage was correlated with a future cell fate as iPSCs or non-reprogrammed cells. These results suggest that Foxd1 is a mediator and indicator of the successful progression of the gene expression program in cell reprogramming.

ORGANISM(S): Mus musculus

PROVIDER: GSE51179 | GEO | 2014/01/11

SECONDARY ACCESSION(S): PRJNA221530

REPOSITORIES: GEO

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Effect of Foxd1 knockdown in the reprogramming process

Project description:It remains unclear how the ectopic expression of defined transcription factors induces dynamic changes in gene expression profiles that establish a pluripotent state during direct cell reprogramming. In the present study, we first identified a temporal gene expression program during the reprogramming process. Promoter analyses then predicted the role of two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of the gene expression program. Knockdown of Foxd1 or Foxo1 reduced the number of induced pluripotent stem cells (iPSCs). The knockout of Foxd1 prevented the downstream transcription program, including the expression of reprogramming marker genes. Interestingly, the expression level of Foxd1 was also transiently increased in a small population of cells in the middle stage of reprogramming. The presence or absence of Foxd1 expression in this stage was correlated with a future cell fate as iPSCs or non-reprogrammed cells. These results suggest that Foxd1 is a mediator and indicator of the successful progression of the gene expression program in cell reprogramming. Mouse embryonic fibroblasts (MEFs) of Foxd1+/+, Foxd1+/- or Foxd1-/- were infected with retroviruses encoding the three transcription factors (Oct4, Sox2 and Klf4) at day 0 and sampled at day 8.

2014-01-11 | E-GEOD-51179 | biostudies-arrayexpress

Gene expression profiling in the reprogramming process

Project description:It remains unclear how the ectopic expression of defined transcription factors induces dynamic changes in gene expression profiles that establish a pluripotent state during direct cell reprogramming. In the present study, we first identified a temporal gene expression program during the reprogramming process. Promoter analyses then predicted the role of two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of the gene expression program. Knockdown of Foxd1 or Foxo1 reduced the number of induced pluripotent stem cells (iPSCs). The knockout of Foxd1 prevented the downstream transcription program, including the expression of reprogramming marker genes. Interestingly, the expression level of Foxd1 was also transiently increased in a small population of cells in the middle stage of reprogramming. The presence or absence of Foxd1 expression in this stage was correlated with a future cell fate as iPSCs or non-reprogrammed cells. These results suggest that Foxd1 is a mediator and indicator of the successful progression of the gene expression program in cell reprogramming. Mouse embryonic fibroblasts (MEFs) were infected with retroviruses encoding either the four transcription factors (Oct4, Sox2, Klf4 and c-Myc) or GFP (control) at day 0 and sampled on the indicated days. Two replicates each.

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Gene expression comparison of E14.5 Foxd1 null and wild type kidneys

Project description:Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. Foxd1 is required during kidney development and its inactivation results in failure of nephron progenitor cell differentiation. Foxd1 is expressed in interstitial cells adjacent to nephron progenitor cells, suggesting an essential role for the progenitor cell niche in nephrogenesis. To better understand how cortical interstitial cells in general, and FOXD1 in particular, influence the progenitor cell niche, we examined the differentiation states of two progenitor cell subtypes in Foxd1-/- tissue. We found that while nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we used microarray analysis and screened for target genes by comparison of Foxd1 null and wild type tissues. We chose the E14.5 timepoint because at this stage nephron differentiation is present in wild type kidneys but absent from Foxd1 null kidneys. We examined genes that were upregulated or downregulated in the Foxd1 null compared to wild type.

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Foxd1 is required for terminal differentiation of anterior hypothalamic neuronal subtypes

Project description:Although the hypothalamus functions as a master homeostat for many behaviors, little is known about the transcriptional networks that control its development. To investigate this question, we analyzed mice deficient for the Forkhead domain transcription factor Foxd1. Foxd1 is selectively expressed in neuroepithelial cells of the prethalamus and hypothalamus prior to the onset of neurogenesis, and is later restricted to neural progenitors of the prethalamus and anterior hypothalamus. During early stages of neurogenesis, we observed that Foxd1-deficient mice showed reduced expression of Six3 and Vax1 in anterior hypothalamus, but overall patterning of the prethalamus and hypothalamus is unaffected. After neurogenesis is complete, however, a progressive reduction and eventual loss of expression of molecular markers of the suprachiasmatic, paraventricular and periventricular hypothalamic is observed. These findings demonstrate that Foxd1 acts in hypothalamic progenitors to allow sustained expression of a subset of genes selectively expressed in mature neurons of the anterior hypothalamus.

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Project description:Cell senescence is a driver of various aging-associated disorders including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (MSCs) and ameliorating osteoarthritis in mice. Targeted knockout of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP interacted with TEA domain transcriptional factor (TEAD) to activate forkhead box D1 (FOXD1) expression. YAP deficiency led to the downregulation of FOXD1, a geroprotective protein. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vectors encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential therapeutic target for gene therapy to alleviate osteoarthritis.

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Loss of neural crest-associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation

Project description:Recent studies suggest that malignant melanoma heterogeneity includes subpopulations of cells with features of multipotent neural crest (NC) cells. Zebrafish and mouse models have shown that reactivation of neural crest-specific pathways determines the invasiveness of melanoma cells. In this study, we show that the neural crest-associated transcription factor FOXD1 plays a key role in invasion and migration capacity of metastatic melanomas both in vivo and in vitro. Gene expression profiling analysis identified on one hand, an upregulation of FOXD1 in NC and melanoma cells, and on the other hand, a downregulation of several genes related to cell invasion in FOXD1 knockdown cells, including MMP9 and RAC1B. Furthermore, we demonstrate that knockdown of RAC1B a tumor-specific isoform of RAC1, significantly impaired cell migration and invasion in melanoma and could abrogate enhanced invasiveness induced by FOXD1 overexpression. We conclude that FOXD1 may influence invasion and migration via indirect regulation of MMP9 and RAC1B alternative splicing in melanoma cells.

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FOXD1 is associated with poor outcome and maintains tumor-promoting enhancer-gene programs in basal-like breast cancer [RNA-seq]

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