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

• Published in: Nature (London) 2011-12, Vol.480 (7377), p.383-386
• Main Authors: Lynch, Vincent J., May, Gemma, Wagner, Günter P.
• Format: Article
• Language: English
• Subjects: 631/208/200; 631/337/572/2102; 631/45/612/822; 631/80/86; Amino Acid Substitution; Amino acids; Analysis; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; CCAAT-Enhancer-Binding Protein-beta - chemistry; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; Control; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Eutherians; Evolution; Evolution & development; Evolution, Molecular; Female; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Genetic aspects; Genetic regulation; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; HeLa Cells; Humanities and Social Sciences; Humans; Kinases; letter; Life sciences; Mammals; Models, Molecular; Molecular and cellular biology; multidisciplinary; Mutation; Natural history; Phosphorylation; Phosphorylation - genetics; Physiological aspects; Placenta; Pregnancy; Protein binding; Protein Conformation; Protein Structure, Tertiary; Proteins; Science; Structure-Activity Relationship; Transcription factors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10595

Evolution of gene regulation Changes in cis -regulatory regions of the genome play an important part in the evolution of gene regulation. Lynch et al . explore the influence of amino acid substitutions in transcription factors on gene regulation. They show how, over evolutionary time, amino acid substitutions in the transcription factor CEBPB in the stem-lineage of placental mammals reorganize the location of key phosphorylation sites, thereby changing the way it responds to cAMP/PKA signalling. There is an emerging consensus that gene regulation evolves through changes in cis -regulatory elements 1 , 2 and transcription factors 3 , 4 , 5 , 6 . 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 4 , 5 , 6 , 7 , 8 , 9 , 10 . Here we show that amino-acid changes in the transcription factor CCAAT/enhancer binding protein-β (CEBPB, also known as C/EBP-β) 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-3β-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.