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. 2008 Feb 26;105(8):2934-9.
doi: 10.1073/pnas.0708670105. Epub 2008 Feb 19.

A systems approach to delineate functions of paralogous transcription factors: role of the Yap family in the DNA damage response

Kai Tan  1 , Hoda Feizi, Colin Luo, Stephanie H Fan, Timothy Ravasi, Trey G Ideker
Affiliations

A systems approach to delineate functions of paralogous transcription factors: role of the Yap family in the DNA damage response

Kai Tan et al. Proc Natl Acad Sci U S A. .

Abstract

Duplication of genes encoding transcription factors plays an essential role in driving phenotypic variation. Because regulation can occur at multiple levels, it is often difficult to discern how each duplicated factor achieves its regulatory specificity. In these cases, a "systems approach" may distinguish the role of each factor by integrating complementary large-scale measurements of the regulatory network. To explore such an approach, we integrate growth phenotypes, promoter binding profiles, and gene expression patterns to model the DNA damage response network controlled by the Yeast-specific AP-1 (YAP) family of transcription factors. This analysis reveals that YAP regulatory specificity is achieved by at least three mechanisms: (i) divergence of DNA-binding sequences into two subfamilies; (ii) condition-specific combinatorial regulation by multiple Yap factors; and (iii) interactions of Yap 1, 4, and 6 with chromatin remodeling proteins. Additional microarray experiments establish that Yap 4 and 6 regulate gene expression through interactions with the histone deacetylase, Hda1. The data further highlight differences among Yap paralogs in terms of their regulatory mode of action (activation vs. repression). This study suggests how other large TF families might be disentangled in the future.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Summary of gene promoters bound by Yap TFs. (A) MMS response. (B) CDDP response. (Left) Number of promoters by each Yap. The three regions represent promoters bound exclusively in the absence of DNA damaging agent (blue), presence of DNA damaging agent (green), or in both conditions (orange). (Right) Changes in Yap promoter binding behaviors. PE, significance of expanded target set compared with negative control; PC, significance of contracted target set.
Fig. 2.
Fig. 2.
Regulatory epistasis. (A) Total number of genes epistatic to Yaps. (B) Representative epistatic genes involving YAP1 in MMS response. Expression changes are colored yellow for up-regulation or blue for down-regulation. *, genes previously known to function in the DNA damage response.
Fig. 3.
Fig. 3.
DNA binding motifs of five Yaps and their phylogeny. Core regions of the motifs are highlighted by a box. IC, information content. Numbers at each branch point are percentage bootstrap values. Motif resources: Yap1/2/4/5/6, this study; Yap8 and Gcn4, ref. ; Yap7, ref. . Yap3 has no reported motif.
Fig. 4.
Fig. 4.
Significant overlaps between Yap target gene sets (P < 0.001). Line width is proportional to −log P. (A) MMS treatment. (B) CDDP treatment. (C) Nominal growth conditions. (D) Enriched functional categories of genes coregulated by pairs of Yaps. Blue, MMS response; orange, CDDP response; turquoise, nominal condition.
Fig. 5.
Fig. 5.
Deletion of HDA1 increases Yap1, 4, and 6 target expression. Shown is the difference in fold change (hda1Δ+MMS/hda1Δ−MMS − WT+MMS/WT−MMS) averaged across all TF targets. Positive control, targets of two TFs (Sko1 and Sut1) known to interact with Hda1. Negative control, targets of three TFs (Dig1, Ecm22, and Rtg3) not predicted to interact with any chromatin remodeling factors in ref. .
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