Meeting Abstract
6.5 Monday, Jan. 4 Evolution of physical interactions between transcription factors HoxA-11 and FOXO1A: thinking beyond cis-regulation. BRAYER, KJ*; LYNCH, VJ; WAGNER, GP; Yale University kathryn.brayer@yale.edu
The cis-regulatory paradigm attributes evolutionary novelty to changes in non-coding DNA sequences. According to the theory, changes in DNA sequence affect the ability of transcription factors to bind regulatory regions leading to changes in gene regulation and novelty. While not incorrect, this theory is limited as it ignores evolutionary change in the transcription factors themselves, thereby ignoring changes that affect DNA binding and interactions with other transcription factors, co-factors, and signaling molecules. Here, we examine the functional evolution of transcription factors involved in the decidualization of endometrial stromal cells, a critical step in the successful establishment of pregnancy. Although the molecular mechanisms that regulate decidualization are poorly understood, the importance of decidual prolactin expression, a derived characteristic of Eutherian mammals, has long been recognized. In humans and many other primates decidual prolactin expression is regulated by a tissue specific promoter comprised of two transposable elements, MER20 and MER39, located upstream of the transcription start site. MER20 contains binding sites for numerous transcription factors, including HoxA-11 and FOXO1A. Recently, we observed phylogenetically derived protein-protein interactions between these two transcription factors in mammals; however, the derived functional interaction, resulting in upregulation of expression from the MER20 promoter, is restricted to Eutherian mammals. Here we examine the evolution of physical interactions between ancestral and derived HoxA-11, FOXO1A and MER20 by testing whether the derived functional interaction involves novel or stronger binding affinity among the molecules or whether it also includes a derived transcriptional activity by the transcription factor proteins. Implications for the evolution of prolactin regulation will be discussed.
