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Original Article |
1,
1 Department of Pathology, University of Florida College of Medicine, Gainesville, Florida
2 Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida
3 Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville Florida
4 Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida
5 Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
* To whom correspondence should be addressed. E-mail: terada{at}pathology.ufl.edu.
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Abstract |
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The capacity for cellular differentiation is governed not only by the repertoire of available transcription factors but the accessibility of cis-regulatory elements. Studying changes in epigenetic modifications during stem cell differentiation will help us to understand how cells maintain or lose differentiation potential. We investigated changes in DNA methylation during the transition of pluripotent embryonic stem (ES) cells into differentiated cell types. Using a methylation-sensitive restriction fingerprinting method, we identified a novel adenine nucleotide (ADP/ATP) translocase gene Ant4 that was selectively hypomethylated and expressed in undifferentiated mouse ES cells. In contrast to other pluripotent stem cell-specific genes such as Oct-4 and Nanog, the Ant4 gene was readily derepressed in differentiated cells after 5-aza-2'-deoxycytidine treatment. Moreover, expression of de novo DNA methyltransferases, Dnmt3a and Dnmt3b, were essential for repression and DNA methylation of the Ant4 gene during ES cell differentiation. While the deduced amino acid sequence of Ant4 is highly homologous to the previously identified Ant isoforms, the expression of Ant4 was uniquely restricted to developing gametes in adult mice, and its promoter hypomethylation was observed only in testis. Additionally, Ant4 was expressed in primordial germ cells. These data indicate that Ant4 is a pluripotent stem cell and germ cell-specific isoform of adenine nucleotide translocase in mouse, and that DNA methylation plays a primary role in its transcriptional silencing in somatic cells.
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