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J. Biol. Chem., Vol. 281, Issue 48, 37034-37044, December 1, 2006

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Antisense Targeting of CXXC Finger Protein 1 Inhibits Genomic Cytosine Methylation and Primitive Hematopoiesis in Zebrafish^*

Suzanne R. L. Young, Christen Mumaw, James A. Marrs, and David G. Skalnik¹

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

CXXC finger protein 1 (CFP1) binds to unmethylated CpG dinucleotides and is a component of the Set1 histone methyltransferase complex. Mice lacking CFP1 suffer a peri-implantation lethal phenotype, and CFP1-deficient embryonic stem cells are viable but unable to differentiate and exhibit a 60-80% decrease in genomic cytosine methylation. A zebrafish homolog of CFP1 has been identified, is 70% similar to murine CFP1, and is widely expressed during development. Zebrafish embryos treated with a zCFP1 antisense morpholino oligonucleotide had little or no circulating red blood cells and exhibited abnormal yolk sac morphology at 48 h post-fertilization. Many of the antisense-treated zebrafish also exhibited cardiac edema, and 14% were dead at 24 h post-fertilization. Morphant zebrafish also exhibited elevated levels of apoptosis, particularly in the intermediate cell mass, the site of primitive erythropoiesis, as well as aberrations in vascular development. Genomic DNA isolated from morphant embryos exhibited a 60% reduction of global genomic cytosine methylation. A similar phenotype was observed with an independent zCFP1 antisense morpholino oligonucleotide, but not following injection of an unrelated control oligonucleotide. The morphant phenotype was rescued when mRNA encoding murine CFP1 was co-injected with the antisense oligonucleotide. Genomic data base analysis reveals the presence of a second version of zebrafish CFP1 (zCFP1b). However, the morphant phenotype observed following specific depletion of zCFP1 indicates that these related genes have nonredundant functions controlling normal zebrafish hematopoiesis and epigenetic regulation. These findings establish the importance of CFP1 during postgastrulation development.

Received for publication, May 11, 2006 , and in revised form, September 11, 2006.

^* This work is supported by the Riley Children's Foundation, the Lilly Foundation, National Science Foundation Grant MCB-0344870 (to D. G. S.), and a predoctoral fellowship (to S. R. L. Y.) by the Midwest Affiliate of the American Heart Association. This work was also supported in part by Grant P40 RR12546 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental video files.

¹ To whom correspondence should be addressed: Cancer Research Bldg., Rm. W327, 1044 W. Walnut St., Indiana University School of Medicine, Indianapolis, IN 46202. Tel.: 317-274-8977; Fax: 317-274-8928; E-mail dskalnik{at}iupui.edu.

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				C. M. Tate, J.-H. Lee, and D. G. Skalnik CXXC Finger Protein 1 Contains Redundant Functional Domains That Support Embryonic Stem Cell Cytosine Methylation, Histone Methylation, and Differentiation Mol. Cell. Biol., July 15, 2009; 29(14): 3817 - 3831. [Abstract] [Full Text] [PDF]