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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.

Pubmed ID: 19433449

Authors

  • Tate CM
  • Lee JH
  • Skalnik DG

Journal

Molecular and cellular biology

Publication Data

July 29, 2009

Associated Grants

  • Agency: NIAID NIH HHS, Id: T32 AI060519
  • Agency: NIAID NIH HHS, Id: T32 AI060519

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