Effects of differentiation on the transcriptional regulation of the FGF- 4 gene: Critical roles played by a distal enhancer

Kimberly A. Lamb, A Angie Rizzino

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34 Citations (Scopus)

Abstract

Embryonal carcinoma (EC) cells are used widely as a model system for studying the expression of developmentally regulated genes, in particular genes that are regulated at the transcriptional level when EC cells differentiate. This review focuses on the molecular mechanisms that govern the transcription of the fibroblast growth factor-4 (FGF-4) gene, which appears to be the first FGF expressed during mammalian development. Interest in this gene has increased considerably with the finding that FGF-4 is essential for mammalian embryogenesis. The FGF-4 gene has also generated considerable interest because it is inhibited at the transcriptional level when EC cells undergo differentiation and because this gene is regulated by a powerful distal enhancer located 3 kb downstream of the transcription start site in the last exon of the gene. Hence, study of the FGF-4 gene is likely to shed light on the molecular mechanisms by which distal enhancers regulate gene expression. In addition to being regulated by the downstream enhancer, the expression of this gene is influenced by a regulatory region located just upstream of the transcription start site, which contains two Sp1 motifs and a CCAAT box motif. Examination of the downstream enhancer has identified three functional cis-regulatory elements: a high mobility group (HMG) protein binding motif, an octamer binding motif, and an Sp1 motif, which are likely to bind Sox-2, Oct-3, and Sp1/Sp3, respectively, in vivo. Interestingly, Sox- 2 and Oct-3 expression, like FGF-4 expression, decreases when EC cells differentiate, which suggests that the loss of these transcription factors is responsible, at least in part, for the transcriptional turn-off of the FGF-4 gene. In view of these and other findings, we present a model for the differential expression of the FGF-4 gene that includes not only the contributions of specific transcription factors, but also the contribution of chromatin structure before and after differentiation.

Original languageEnglish (US)
Pages (from-to)218-224
Number of pages7
JournalMolecular Reproduction and Development
Volume51
Issue number2
DOIs
StatePublished - Oct 1 1998

Fingerprint

Fibroblast Growth Factor 4
Embryonal Carcinoma Stem Cells
Genes
Transcription Initiation Site
Transcription Factors
High Mobility Group Proteins
Gene Expression
Amino Acid Motifs
Nucleic Acid Regulatory Sequences
Protein Binding
Chromatin
Embryonic Development
Cell Differentiation
Exons

Keywords

  • Chromatin remodeling complex
  • Embryonal carcinoma cell
  • Fibroblast growth factor-4
  • Gene expression
  • Oct- 3
  • Sox2

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

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title = "Effects of differentiation on the transcriptional regulation of the FGF- 4 gene: Critical roles played by a distal enhancer",
abstract = "Embryonal carcinoma (EC) cells are used widely as a model system for studying the expression of developmentally regulated genes, in particular genes that are regulated at the transcriptional level when EC cells differentiate. This review focuses on the molecular mechanisms that govern the transcription of the fibroblast growth factor-4 (FGF-4) gene, which appears to be the first FGF expressed during mammalian development. Interest in this gene has increased considerably with the finding that FGF-4 is essential for mammalian embryogenesis. The FGF-4 gene has also generated considerable interest because it is inhibited at the transcriptional level when EC cells undergo differentiation and because this gene is regulated by a powerful distal enhancer located 3 kb downstream of the transcription start site in the last exon of the gene. Hence, study of the FGF-4 gene is likely to shed light on the molecular mechanisms by which distal enhancers regulate gene expression. In addition to being regulated by the downstream enhancer, the expression of this gene is influenced by a regulatory region located just upstream of the transcription start site, which contains two Sp1 motifs and a CCAAT box motif. Examination of the downstream enhancer has identified three functional cis-regulatory elements: a high mobility group (HMG) protein binding motif, an octamer binding motif, and an Sp1 motif, which are likely to bind Sox-2, Oct-3, and Sp1/Sp3, respectively, in vivo. Interestingly, Sox- 2 and Oct-3 expression, like FGF-4 expression, decreases when EC cells differentiate, which suggests that the loss of these transcription factors is responsible, at least in part, for the transcriptional turn-off of the FGF-4 gene. In view of these and other findings, we present a model for the differential expression of the FGF-4 gene that includes not only the contributions of specific transcription factors, but also the contribution of chromatin structure before and after differentiation.",
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N2 - Embryonal carcinoma (EC) cells are used widely as a model system for studying the expression of developmentally regulated genes, in particular genes that are regulated at the transcriptional level when EC cells differentiate. This review focuses on the molecular mechanisms that govern the transcription of the fibroblast growth factor-4 (FGF-4) gene, which appears to be the first FGF expressed during mammalian development. Interest in this gene has increased considerably with the finding that FGF-4 is essential for mammalian embryogenesis. The FGF-4 gene has also generated considerable interest because it is inhibited at the transcriptional level when EC cells undergo differentiation and because this gene is regulated by a powerful distal enhancer located 3 kb downstream of the transcription start site in the last exon of the gene. Hence, study of the FGF-4 gene is likely to shed light on the molecular mechanisms by which distal enhancers regulate gene expression. In addition to being regulated by the downstream enhancer, the expression of this gene is influenced by a regulatory region located just upstream of the transcription start site, which contains two Sp1 motifs and a CCAAT box motif. Examination of the downstream enhancer has identified three functional cis-regulatory elements: a high mobility group (HMG) protein binding motif, an octamer binding motif, and an Sp1 motif, which are likely to bind Sox-2, Oct-3, and Sp1/Sp3, respectively, in vivo. Interestingly, Sox- 2 and Oct-3 expression, like FGF-4 expression, decreases when EC cells differentiate, which suggests that the loss of these transcription factors is responsible, at least in part, for the transcriptional turn-off of the FGF-4 gene. In view of these and other findings, we present a model for the differential expression of the FGF-4 gene that includes not only the contributions of specific transcription factors, but also the contribution of chromatin structure before and after differentiation.

AB - Embryonal carcinoma (EC) cells are used widely as a model system for studying the expression of developmentally regulated genes, in particular genes that are regulated at the transcriptional level when EC cells differentiate. This review focuses on the molecular mechanisms that govern the transcription of the fibroblast growth factor-4 (FGF-4) gene, which appears to be the first FGF expressed during mammalian development. Interest in this gene has increased considerably with the finding that FGF-4 is essential for mammalian embryogenesis. The FGF-4 gene has also generated considerable interest because it is inhibited at the transcriptional level when EC cells undergo differentiation and because this gene is regulated by a powerful distal enhancer located 3 kb downstream of the transcription start site in the last exon of the gene. Hence, study of the FGF-4 gene is likely to shed light on the molecular mechanisms by which distal enhancers regulate gene expression. In addition to being regulated by the downstream enhancer, the expression of this gene is influenced by a regulatory region located just upstream of the transcription start site, which contains two Sp1 motifs and a CCAAT box motif. Examination of the downstream enhancer has identified three functional cis-regulatory elements: a high mobility group (HMG) protein binding motif, an octamer binding motif, and an Sp1 motif, which are likely to bind Sox-2, Oct-3, and Sp1/Sp3, respectively, in vivo. Interestingly, Sox- 2 and Oct-3 expression, like FGF-4 expression, decreases when EC cells differentiate, which suggests that the loss of these transcription factors is responsible, at least in part, for the transcriptional turn-off of the FGF-4 gene. In view of these and other findings, we present a model for the differential expression of the FGF-4 gene that includes not only the contributions of specific transcription factors, but also the contribution of chromatin structure before and after differentiation.

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