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J. Biol. Chem., Vol. 281, Issue 51, 39081-39087, December 22, 2006

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Cyclophilin A Protects Peg3 from Hypermethylation and Inactive Histone Modification^*

Ying-Chun Lu, Jun Song, Hee-Yeon Cho, Guoping Fan^¶, Kazunari K. Yokoyama^||, and Robert Chiu^**1

From the Dental Research Institute, UCLA School of Dentistry and ^¶Department of Human Genetics, UCLA, Los Angeles, California 90095, ^||Gene Engineering Division, BioResource Center, RIKEN, Tsukuba, Ibaraki 305, Japan, ^**Department of Surgery/Oncology, UCLA School of Medicine, and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095

Imprinted genes are expressed from only one of the parental alleles and are marked epigenetically by DNA methylation and histone modifications. Disruption of normal imprinting leads to abnormal embryogenesis, certain inherited diseases, and is associated with various cancers. In the context of screening for the gene(s) responsible for the alteration of phenotype in cyclophilin A knockdown (CypA-KD) P19 cells, we observed a silent paternally expressed gene, Peg3. Treatment of CypA-KD P19 cells with the DNA demethylating agent 5-aza-dC reversed the silencing of Peg3 biallelically. Genomic bisulfite sequencing and methylation-specific PCR revealed DNA hypermethylation in CypA-KD P19 cells, as the normally unmethylated paternal allele acquired methylation that resulted in biallelic methylation of Peg3. Chromatin immunoprecipitation assays indicated a loss of acetylation and a gain of lysine 9 trimethylation in histone 3, as well as enhanced DNA methyltransferase 1 and MBD2 binding on the cytosine-guanine dinucleotide (CpG) islands of Peg3. Our results indicate that DNA hypermethylation on the paternal allele and allele-specific acquisition of histone methylation leads to silencing of Peg3 in CypA-KD P19 cells. This study is the first demonstration of the epigenetic function of CypA in protecting the paternal allele of Peg3 from DNA methylation and inactive histone modifications.

Received for publication, July 14, 2006 , and in revised form, September 29, 2006.

^* This work was supported by Grant CA66746 from the National Cancer Institute. 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.

¹ To whom correspondence should be addressed. Tel.: 310-825-0535; E-mail: rchiu{at}dent.ucla.edu.

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