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Nature. 2011 Nov 13;480(7377):383-6. doi: 10.1038/nature10595.

Regulatory evolution through divergence of a phosphoswitch in the transcription factor CEBPB.

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Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut 06511, USA.


There is an emerging consensus that gene regulation evolves through changes in cis-regulatory elements and transcription factors. Although it is clear how nucleotide substitutions in cis-regulatory elements affect gene expression, it is not clear how amino-acid substitutions in transcription factors influence gene regulation. Here we show that amino-acid changes in the transcription factor CCAAT/enhancer binding protein-╬▓ (CEBPB, also known as C/EBP-╬▓) in the stem-lineage of placental mammals changed the way it responds to cyclic AMP/protein kinase A (cAMP/PKA) signalling. By functionally analysing resurrected ancestral proteins, we identify three amino-acid substitutions in an internal regulatory domain of CEBPB that are responsible for the novel function. These amino-acid substitutions reorganize the location of key phosphorylation sites, introducing a new site and removing two ancestral sites, reversing the response of CEBPB to GSK-3╬▓-mediated phosphorylation from repression to activation. We conclude that changing the response of transcription factors to signalling pathways can be an important mechanism of gene regulatory evolution.

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