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Science  02 Aug 2013:
Vol. 341, Issue 6145, pp. 436
DOI: 10.1126/science.341.6145.436-b

Changes in the regulation of gene expression can result in changes in organismal phenotypes. Nakagawa et al. have used phylogenetic analysis and biochemical measurement to study DNA binding specificity changes in the forkhead box (Fox) family of transcription factors. This family is present in a wide range of species and is one of the largest classes of transcription factors in humans. They used phylogenetic inference methods to examine the relationship of Fox domain sequences spanning 623 genes from 65 species, and they characterized binding specificity in vitro for 21 Fox proteins and combined this with published binding data for 9 proteins. They found that changes in specificity from canonical forkhead primary (FkhP) and forkhead secondary (FkhS) motifs to alternative DNA sequences have occurred separately in three different Fox subfamily lineages. In fungal Fox3 proteins, two specificities have arisen, FHL-3 and FVH, but only FVH binding involves the mutation of residues involved in DNA recognition. In the metazoan FoxM subfamily, proteins retain specificity for FkhP and FkhS but are also able to bind an FHL motif, whereas in the holozoan FoxN subfamily, some proteins exhibit a similar bispecificity, yet others have lost the ability to bind the canonical sites and only bind FHL-N. Fox domains that display bispecific binding are probably able to switch between two conformations with distinct DNA binding specificities. Such bispecificity may be central in the evolution of transcriptional regulatory networks.

Proc. Natl. Acad. Sci. U.S.A. 110, 10.1073/pnas.1310430110 (2013).

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