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Molecular and Cellular Biology, July 2009, p. 3817-3831, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00243-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

CXXC Finger Protein 1 Contains Redundant Functional Domains That Support Embryonic Stem Cell Cytosine Methylation, Histone Methylation, and Differentiation{triangledown}

Courtney M. Tate, Jeong-Heon Lee, and David G. Skalnik*

Herman B Wells Center for Pediatric Research, Section of Pediatric Hematology/Oncology, Departments of Pediatrics and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202

Received 24 February 2009/ Returned for modification 14 April 2009/ Accepted 1 May 2009

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 [Cfp11-367]) or the carboxyl half of Cfp1 (Cfp1361-656) 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 Cfp11-367 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 Cfp1361-656 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.

* Corresponding author. Mailing address: Cancer Research Institute, Indiana University School of Medicine, 1044 West Walnut St., Room 327, Indianapolis, IN 46202. Phone: (317) 274-8977. Fax: (317) 274-8679. E-mail: dskalnik{at}iupui.edu

{triangledown} Published ahead of print on 11 May 2009.

Molecular and Cellular Biology, July 2009, p. 3817-3831, Vol. 29, No. 14
0270-7306/09/$08.00+0     doi:10.1128/MCB.00243-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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