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Bipartite Recognition of DNA by TCF/Pangolin Is Remarkably Flexible and Contributes to Transcriptional Responsiveness and Tissue Specificity of Wingless Signaling


Regulation of gene expression is controlled in large part by proteins known as transcription factors, which bind to specific DNA sequences in the genome. The DNA binding domains of transcription factors recognize short stretches (5–11 base pairs) of DNA with considerable sequence degeneracy. This means that a single DNA binding domain, on its own, cannot find its targets in the vast excess of genomic sequence. We are studying this question using TCF/Pangolin, a Drosophila transcription factor that mediates Wnt/β-catenin signaling, an important developmental cell-cell communication pathway. TCF/Pangolin contains two DNA binding domains that bind to a pair of DNA motifs known as HMG and Helper sites. We used a combination of biochemistry, genetics and bioinformatics to elucidate the spacing and orientation constraints of HMG-Helper site pairs. We found that HMG-Helper site spacing/orientation influenced the sensitivity of a target to Wnt signaling, as well as its tissue-responsiveness. We used this information to improve our ability to search the Drosophila genome for Wnt targets, one of which was activated by the pathway in the fly ring gland, the major endocrine organ in insects. Our work is relevant to related mammalian TCF family members, which are implicated in development, stem cell biology and the progression of cancer.


Vyšlo v časopise: Bipartite Recognition of DNA by TCF/Pangolin Is Remarkably Flexible and Contributes to Transcriptional Responsiveness and Tissue Specificity of Wingless Signaling. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004591
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004591

Souhrn

Regulation of gene expression is controlled in large part by proteins known as transcription factors, which bind to specific DNA sequences in the genome. The DNA binding domains of transcription factors recognize short stretches (5–11 base pairs) of DNA with considerable sequence degeneracy. This means that a single DNA binding domain, on its own, cannot find its targets in the vast excess of genomic sequence. We are studying this question using TCF/Pangolin, a Drosophila transcription factor that mediates Wnt/β-catenin signaling, an important developmental cell-cell communication pathway. TCF/Pangolin contains two DNA binding domains that bind to a pair of DNA motifs known as HMG and Helper sites. We used a combination of biochemistry, genetics and bioinformatics to elucidate the spacing and orientation constraints of HMG-Helper site pairs. We found that HMG-Helper site spacing/orientation influenced the sensitivity of a target to Wnt signaling, as well as its tissue-responsiveness. We used this information to improve our ability to search the Drosophila genome for Wnt targets, one of which was activated by the pathway in the fly ring gland, the major endocrine organ in insects. Our work is relevant to related mammalian TCF family members, which are implicated in development, stem cell biology and the progression of cancer.


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