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The wind rose of human keratinocyte cell fate.

Wu N, Gidrol X - Cell. Mol. Life Sci. (2014)

Bottom Line: Although pieces of information have been obtained from single-gene function investigations, the entire picture of the molecular mechanisms involved in the regulation of epithelial homeostasis is still mysterious.Growing data indicate that gene networks rather than single "master" genes dictate cell fate.Through further analysis of the existing data on epithelial tumorigenesis and induced pluripotent stem cells, we propose a wind rose model of cell fate that is based on a balance between these two different networks that ultimately control human keratinocyte fate and epidermal homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Univ. Grenoble Alpes, iRTSV-BGE, 38000, Grenoble, France, ning.wu@ircm.qc.ca.

ABSTRACT
Extensive efforts have been made to understand the molecular actors that control epithelial cell fate. Although pieces of information have been obtained from single-gene function investigations, the entire picture of the molecular mechanisms involved in the regulation of epithelial homeostasis is still mysterious. Growing data indicate that gene networks rather than single "master" genes dictate cell fate. In an attempt to characterize such gene networks, we have been investigating the human keratinocyte proliferation and differentiation genes that act downstream of the transcription factor p63, a major regulator of epidermal homeostasis. We identified two networks: the cell cycle network that controls cell proliferation and the keratinocyte cell fate network. Through further analysis of the existing data on epithelial tumorigenesis and induced pluripotent stem cells, we propose a wind rose model of cell fate that is based on a balance between these two different networks that ultimately control human keratinocyte fate and epidermal homeostasis.

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Keratinocyte cell fate network. Genetic networks involved in keratinocyte differentiation consist of common genes that are oppositely modulated in MYC- or p63-knockdown keratinocytes. The lists of genes were obtained from transcriptome profiling of HaCaT cells treated with a siRNA targeting MYC (siMYC) a or a siRNA targeting all isoforms of p63 (siP63) b after 48 h. The complete list of genes can be found in Wu et al. [21]. Networks were extracted using the Ingenuity Pathway Assist software (http://www.ingenuity.com/products/ipa). Nodes (genes or proteins) in the networks are indicated by different shapes (biological functions) and colors (red indicates up-regulated, and green represents down-regulated). Edges are represented as solid or dashed lines to indicate direct and indirect interactions, respectively
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Fig2: Keratinocyte cell fate network. Genetic networks involved in keratinocyte differentiation consist of common genes that are oppositely modulated in MYC- or p63-knockdown keratinocytes. The lists of genes were obtained from transcriptome profiling of HaCaT cells treated with a siRNA targeting MYC (siMYC) a or a siRNA targeting all isoforms of p63 (siP63) b after 48 h. The complete list of genes can be found in Wu et al. [21]. Networks were extracted using the Ingenuity Pathway Assist software (http://www.ingenuity.com/products/ipa). Nodes (genes or proteins) in the networks are indicated by different shapes (biological functions) and colors (red indicates up-regulated, and green represents down-regulated). Edges are represented as solid or dashed lines to indicate direct and indirect interactions, respectively

Mentions: We observed that the ablation of p63 inhibited keratinocyte differentiation, while cells lacking MYC were still able to differentiate [21]. This confirmed that the differentiation defect was not due to tissue hypoplasia. Again, we compared the expression profiles in MYC-depleted keratinocytes with those of cells lacking p63 and identified a gene network common to p63- and MYC-knockdown keratinocytes that was oppositely regulated. This network is composed mainly of cell adhesion- and migration-related genes that are located in the cytoplasm, plasma membrane, and even secreted outside of cells (Fig. 2). Further studies demonstrated that this network plays a significant role in keratinocyte cell fate; therefore, we named it the keratinocyte cell fate (KCF) network. To summarize, the KCF network was up-regulated in keratinocytes lacking MYC (Fig. 2a) and down-regulated in p63-depleted keratinocytes (Fig. 2b). We cultured HaCaT cells in a low calcium concentration medium until confluence to induce the onset of keratinocyte differentiation. Therefore, cells began to differentiate only when they received confluence signals upon contact with other cells, and, as a consequence, it makes sense that this network is up-regulated upon keratinocyte differentiation. Strikingly, all studies on the analysis of p63 target sites in the human genome have shown enrichment in genes involved in cell adhesion: 336 genes (p value = 3.73E−12) [18] and 286 genes (p value = 1.52E−11) [19]. Furthermore, Carroll et al. [25] demonstrated that knockdown of p63 in mammary epithelial cells caused the downregulation of cell adhesion-associated genes. Lastly, numerous studies have established a clear link between cell adhesion and differentiation [26–28].Fig. 2


The wind rose of human keratinocyte cell fate.

Wu N, Gidrol X - Cell. Mol. Life Sci. (2014)

Keratinocyte cell fate network. Genetic networks involved in keratinocyte differentiation consist of common genes that are oppositely modulated in MYC- or p63-knockdown keratinocytes. The lists of genes were obtained from transcriptome profiling of HaCaT cells treated with a siRNA targeting MYC (siMYC) a or a siRNA targeting all isoforms of p63 (siP63) b after 48 h. The complete list of genes can be found in Wu et al. [21]. Networks were extracted using the Ingenuity Pathway Assist software (http://www.ingenuity.com/products/ipa). Nodes (genes or proteins) in the networks are indicated by different shapes (biological functions) and colors (red indicates up-regulated, and green represents down-regulated). Edges are represented as solid or dashed lines to indicate direct and indirect interactions, respectively
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4233109&req=5

Fig2: Keratinocyte cell fate network. Genetic networks involved in keratinocyte differentiation consist of common genes that are oppositely modulated in MYC- or p63-knockdown keratinocytes. The lists of genes were obtained from transcriptome profiling of HaCaT cells treated with a siRNA targeting MYC (siMYC) a or a siRNA targeting all isoforms of p63 (siP63) b after 48 h. The complete list of genes can be found in Wu et al. [21]. Networks were extracted using the Ingenuity Pathway Assist software (http://www.ingenuity.com/products/ipa). Nodes (genes or proteins) in the networks are indicated by different shapes (biological functions) and colors (red indicates up-regulated, and green represents down-regulated). Edges are represented as solid or dashed lines to indicate direct and indirect interactions, respectively
Mentions: We observed that the ablation of p63 inhibited keratinocyte differentiation, while cells lacking MYC were still able to differentiate [21]. This confirmed that the differentiation defect was not due to tissue hypoplasia. Again, we compared the expression profiles in MYC-depleted keratinocytes with those of cells lacking p63 and identified a gene network common to p63- and MYC-knockdown keratinocytes that was oppositely regulated. This network is composed mainly of cell adhesion- and migration-related genes that are located in the cytoplasm, plasma membrane, and even secreted outside of cells (Fig. 2). Further studies demonstrated that this network plays a significant role in keratinocyte cell fate; therefore, we named it the keratinocyte cell fate (KCF) network. To summarize, the KCF network was up-regulated in keratinocytes lacking MYC (Fig. 2a) and down-regulated in p63-depleted keratinocytes (Fig. 2b). We cultured HaCaT cells in a low calcium concentration medium until confluence to induce the onset of keratinocyte differentiation. Therefore, cells began to differentiate only when they received confluence signals upon contact with other cells, and, as a consequence, it makes sense that this network is up-regulated upon keratinocyte differentiation. Strikingly, all studies on the analysis of p63 target sites in the human genome have shown enrichment in genes involved in cell adhesion: 336 genes (p value = 3.73E−12) [18] and 286 genes (p value = 1.52E−11) [19]. Furthermore, Carroll et al. [25] demonstrated that knockdown of p63 in mammary epithelial cells caused the downregulation of cell adhesion-associated genes. Lastly, numerous studies have established a clear link between cell adhesion and differentiation [26–28].Fig. 2

Bottom Line: Although pieces of information have been obtained from single-gene function investigations, the entire picture of the molecular mechanisms involved in the regulation of epithelial homeostasis is still mysterious.Growing data indicate that gene networks rather than single "master" genes dictate cell fate.Through further analysis of the existing data on epithelial tumorigenesis and induced pluripotent stem cells, we propose a wind rose model of cell fate that is based on a balance between these two different networks that ultimately control human keratinocyte fate and epidermal homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Univ. Grenoble Alpes, iRTSV-BGE, 38000, Grenoble, France, ning.wu@ircm.qc.ca.

ABSTRACT
Extensive efforts have been made to understand the molecular actors that control epithelial cell fate. Although pieces of information have been obtained from single-gene function investigations, the entire picture of the molecular mechanisms involved in the regulation of epithelial homeostasis is still mysterious. Growing data indicate that gene networks rather than single "master" genes dictate cell fate. In an attempt to characterize such gene networks, we have been investigating the human keratinocyte proliferation and differentiation genes that act downstream of the transcription factor p63, a major regulator of epidermal homeostasis. We identified two networks: the cell cycle network that controls cell proliferation and the keratinocyte cell fate network. Through further analysis of the existing data on epithelial tumorigenesis and induced pluripotent stem cells, we propose a wind rose model of cell fate that is based on a balance between these two different networks that ultimately control human keratinocyte fate and epidermal homeostasis.

Show MeSH
Related in: MedlinePlus