Limits...
A systematic approach identifies FOXA1 as a key factor in the loss of epithelial traits during the epithelial-to-mesenchymal transition in lung cancer.

Wang H, Meyer CA, Fei T, Wang G, Zhang F, Liu XS - BMC Genomics (2013)

Bottom Line: Among the transcription factors tested, impact scores identified the forkhead box protein A1 (FOXA1) as the most significant transcription factor in the epithelial-to-mesenchymal transition.Several critical epithelial-to-mesenchymal transition effectors involved in cellular adhesion and cellular communication were identified in the regulatory network of FOXA1, including FOXA2, FGA, FGB, FGG, and FGL1.Further, this study demonstrates how ChIP-Seq and expression data could be integrated to delineate the impact of transcription factors on a specific biological process.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China. wanghaiyun@tongji.edu.cn.

ABSTRACT

Background: The epithelial-to-mesenchymal transition is an important mechanism in cancer metastasis. Although transcription factors including SNAIL, SLUG, and TWIST1 regulate the epithelial-to-mesenchymal transition, other unknown transcription factors could also be involved. Identification of the full complement of transcription factors is essential for a more complete understanding of gene regulation in this process. Chromatin immunoprecipitation-sequencing (ChIP-Seq) technologies have been used to detect genome-wide binding of transcription factors; here, we developed a systematic approach to integrate existing ChIP-Seq and transcriptome data. We scanned multiple transcription factors to investigate their functional impact on the epithelial-to-mesenchymal transition in the human A549 lung adenocarcinoma cell line.

Results: Among the transcription factors tested, impact scores identified the forkhead box protein A1 (FOXA1) as the most significant transcription factor in the epithelial-to-mesenchymal transition. FOXA1 physically associates with the promoters of its predicted target genes. Several critical epithelial-to-mesenchymal transition effectors involved in cellular adhesion and cellular communication were identified in the regulatory network of FOXA1, including FOXA2, FGA, FGB, FGG, and FGL1. The implication of FOXA1 in the epithelial-to-mesenchymal transition via its regulatory network indicates that FOXA1 may play an important role in the initiation of lung cancer metastasis.

Conclusions: We identified FOXA1 as a potentially important transcription factor and negative regulator in the initial stages of lung cancer metastasis. FOXA1 may modulate the epithelial-to-mesenchymal transition via its transcriptional regulatory network. Further, this study demonstrates how ChIP-Seq and expression data could be integrated to delineate the impact of transcription factors on a specific biological process.

Show MeSH

Related in: MedlinePlus

FOXA1 binding sites in the TSS of FGA, FGB, FGG, FGL1 and FOXA2. Binding sites in A)FGA, FGB, FGG, B)FGL1 and C)FOXA2 were identified in A549 cells by analysis of ChIP-Seq data. The boxed sites indicate the TSS of genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3852829&req=5

Figure 4: FOXA1 binding sites in the TSS of FGA, FGB, FGG, FGL1 and FOXA2. Binding sites in A)FGA, FGB, FGG, B)FGL1 and C)FOXA2 were identified in A549 cells by analysis of ChIP-Seq data. The boxed sites indicate the TSS of genes.

Mentions: Four downregulated genes that enriched cell communication, nectin adhesion, and focal adhesion kinase and fibrinogen complex signaling are related to the loss of epithelial traits in metastasis initiation. FGA, FGB and FGL1 were involved in multiple EMT-related functions (Table 2), and FGG was also identified with a less stringent q value threshold. FGA/FGB/FGG encode the alpha/beta/gamma components of fibrinogen, a blood-borne glycoprotein comprised of three pairs of non-identical polypeptide chains. Fibrinogen is cleaved by thrombin following vascular injury to form fibrin, the most abundant component of blood clots [24]. In addition, fibrinogen induces endothelial cell adhesion and spreading via the release of endogenous matrix proteins and the recruitment of more than one integrin receptor [25]. FGL1 also encodes a member of the fibrinogen family. FGA, FGB, FGG and FGL1 were downregulated during EMT of lung cancer (Figure 3) and were mapped to the GO term ‘Fibrinogen complex’. ChIP-Seq data from A549 cells showed that FOXA1 was strongly bound to TSS of these genes (Figure 4A-B). No binding sites were found at the TSS of these genes in the human breast adenocarcinoma cell line MCF7 or in the human prostate adenocarcinoma cell line LNCaP (Figure 5), suggesting that the regulatory role of FOXA1 in breast and prostate cancer might differ from that of lung and liver cancer. Thus, FGA, FGB, FGG and FGL1 could be important direct target genes of FOXA1 that are involved in EMT of lung and liver cancer specifically.


A systematic approach identifies FOXA1 as a key factor in the loss of epithelial traits during the epithelial-to-mesenchymal transition in lung cancer.

Wang H, Meyer CA, Fei T, Wang G, Zhang F, Liu XS - BMC Genomics (2013)

FOXA1 binding sites in the TSS of FGA, FGB, FGG, FGL1 and FOXA2. Binding sites in A)FGA, FGB, FGG, B)FGL1 and C)FOXA2 were identified in A549 cells by analysis of ChIP-Seq data. The boxed sites indicate the TSS of genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852829&req=5

Figure 4: FOXA1 binding sites in the TSS of FGA, FGB, FGG, FGL1 and FOXA2. Binding sites in A)FGA, FGB, FGG, B)FGL1 and C)FOXA2 were identified in A549 cells by analysis of ChIP-Seq data. The boxed sites indicate the TSS of genes.
Mentions: Four downregulated genes that enriched cell communication, nectin adhesion, and focal adhesion kinase and fibrinogen complex signaling are related to the loss of epithelial traits in metastasis initiation. FGA, FGB and FGL1 were involved in multiple EMT-related functions (Table 2), and FGG was also identified with a less stringent q value threshold. FGA/FGB/FGG encode the alpha/beta/gamma components of fibrinogen, a blood-borne glycoprotein comprised of three pairs of non-identical polypeptide chains. Fibrinogen is cleaved by thrombin following vascular injury to form fibrin, the most abundant component of blood clots [24]. In addition, fibrinogen induces endothelial cell adhesion and spreading via the release of endogenous matrix proteins and the recruitment of more than one integrin receptor [25]. FGL1 also encodes a member of the fibrinogen family. FGA, FGB, FGG and FGL1 were downregulated during EMT of lung cancer (Figure 3) and were mapped to the GO term ‘Fibrinogen complex’. ChIP-Seq data from A549 cells showed that FOXA1 was strongly bound to TSS of these genes (Figure 4A-B). No binding sites were found at the TSS of these genes in the human breast adenocarcinoma cell line MCF7 or in the human prostate adenocarcinoma cell line LNCaP (Figure 5), suggesting that the regulatory role of FOXA1 in breast and prostate cancer might differ from that of lung and liver cancer. Thus, FGA, FGB, FGG and FGL1 could be important direct target genes of FOXA1 that are involved in EMT of lung and liver cancer specifically.

Bottom Line: Among the transcription factors tested, impact scores identified the forkhead box protein A1 (FOXA1) as the most significant transcription factor in the epithelial-to-mesenchymal transition.Several critical epithelial-to-mesenchymal transition effectors involved in cellular adhesion and cellular communication were identified in the regulatory network of FOXA1, including FOXA2, FGA, FGB, FGG, and FGL1.Further, this study demonstrates how ChIP-Seq and expression data could be integrated to delineate the impact of transcription factors on a specific biological process.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Life Science and Technology, Tongji University, Shanghai 200092, China. wanghaiyun@tongji.edu.cn.

ABSTRACT

Background: The epithelial-to-mesenchymal transition is an important mechanism in cancer metastasis. Although transcription factors including SNAIL, SLUG, and TWIST1 regulate the epithelial-to-mesenchymal transition, other unknown transcription factors could also be involved. Identification of the full complement of transcription factors is essential for a more complete understanding of gene regulation in this process. Chromatin immunoprecipitation-sequencing (ChIP-Seq) technologies have been used to detect genome-wide binding of transcription factors; here, we developed a systematic approach to integrate existing ChIP-Seq and transcriptome data. We scanned multiple transcription factors to investigate their functional impact on the epithelial-to-mesenchymal transition in the human A549 lung adenocarcinoma cell line.

Results: Among the transcription factors tested, impact scores identified the forkhead box protein A1 (FOXA1) as the most significant transcription factor in the epithelial-to-mesenchymal transition. FOXA1 physically associates with the promoters of its predicted target genes. Several critical epithelial-to-mesenchymal transition effectors involved in cellular adhesion and cellular communication were identified in the regulatory network of FOXA1, including FOXA2, FGA, FGB, FGG, and FGL1. The implication of FOXA1 in the epithelial-to-mesenchymal transition via its regulatory network indicates that FOXA1 may play an important role in the initiation of lung cancer metastasis.

Conclusions: We identified FOXA1 as a potentially important transcription factor and negative regulator in the initial stages of lung cancer metastasis. FOXA1 may modulate the epithelial-to-mesenchymal transition via its transcriptional regulatory network. Further, this study demonstrates how ChIP-Seq and expression data could be integrated to delineate the impact of transcription factors on a specific biological process.

Show MeSH
Related in: MedlinePlus