CXXC finger protein 1 contains redundant functional domains that support embryonic stem cell cytosine methylation, histone methylation, and differentiation.

CXXC finger protein 1 (Cfp1) is a regulator of both cytosine methylation and histone methylation. Murine embryonic stem (ES) cells lacking Cfp1 exhibit a decreased plating efficiency, decreased cytosine methylation, elevated global levels of histone H3-Lys4 trimethylation, and a failure to differentiate in vitro. Remarkably, transfection studies reveal that expression ...
of either the amino half of Cfp1 (amino acids 1 to 367 [Cfp1(1-367)]) or the carboxyl half of Cfp1 (Cfp1(361-656)) is sufficient to correct all of the defects observed with ES cells that lack Cfp1. However, a point mutation (C169A) that abolishes DNA-binding activity of Cfp1 ablates the rescue activity of the Cfp1(1-367) fragment, and a point mutation (C375A) that abolishes the interaction of Cfp1 with the Setd1 histone H3-Lys4 methyltransferase complexes ablates the rescue activity of the Cfp1(361-656) fragment. Introduction of both the C169A and C375A point mutations ablates the rescue activity of the full-length Cfp1 protein. These results indicate that retention of either the Cfp1 DNA-binding domain or Setd1 interaction domain is required for Cfp1 rescue activity, and they illustrate the functional complexity of this critical epigenetic regulator. A model is presented for how epigenetic cross talk may explain the finding of redundant functional domains within Cfp1.
Mesh Terms:
Amino Acid Sequence, Amino Acid Substitution, Animals, Base Sequence, Binding Sites, Cell Differentiation, Cell Line, Cytosine, DNA Methylation, DNA Primers, DNA-Binding Proteins, Embryonic Stem Cells, Epigenesis, Genetic, Histones, Humans, Mice, Mice, Knockout, Models, Biological, Molecular Sequence Data, Mutagenesis, Site-Directed, Peptide Fragments, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Trans-Activators, Transfection
Mol. Cell. Biol.
Date: Jul. 01, 2009
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