Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression.
During cellular differentiation, both permissive and repressive epigenetic modifications must be negotiated to create cell-type-specific gene expression patterns. The T-box transcription factor family is important in numerous developmental systems ranging from embryogenesis to the differentiation of adult tissues. By analyzing point mutations in conserved sequences in the T-box DNA-binding domain, we found that two overlapping, but physically separable regions are required for the physical and functional interaction with H3K27-demethylase and H3K4-methyltransferase activities. Importantly, the ability to associate with these histone-modifying complexes is a conserved function for the T-box family. These novel mechanisms for T-box-mediated epigenetic regulation are essential, because point mutations that disrupt these interactions are found in a diverse array of human developmental genetic diseases.
Miller
Sara A
SA
Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 98195, USA.
Huang
Albert C
AC
Miazgowicz
Michael M
MM
Brassil
Margaret M
MM
Weinmann
Amy S
AS
D000818:Animals; D002460:Cell Line; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D050437:Genes, Developmental / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*
D020825:T-Box Domain Proteins; D010089:Oxidoreductases, N-Demethylating; D011495:Histone-Lysine N-Methyltransferase