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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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  • 1Yale Systems Biology Institute and Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut 06511, USA. vincent.j.lynch@yale.edu

Abstract

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.

PMID:
22080951
[PubMed - indexed for MEDLINE]
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