DNA Methylation Is Required for Silencing of Ant4 , an Adenine Nucleotide Translocase Selectively Expressed in Mouse Embryonic Stem Cells and Germ Cells
Abstract
The capacity for cellular differentiation is governed not only by the repertoire of available transcription factors but by the accessibility of cis-regulatory elements. Studying changes in epigenetic modifications during stem cell differentiation will help us understand how cells maintain or lose differentiation potential. We investigated changes in DNA methylation during the transition of pluripotent embryonic stem cells (ESCs) 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 ESCs. 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 was essential for repression and DNA methylation of the Ant4 gene during ESC differentiation. Although 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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Slc25a31 encodes ANT4, which at least in some mouse tissues may compensate for absence of ANT1 and ANT2.
“Moreover, Slc25a31 encodes another ANT isoform (i.e., ANT4), that (at least in some mouse tissues) may compensate for the absence of ANT1 and ANT2 [393, 394].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [394]
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- Authors
- Rodić, N., Oka, M., Hamazaki, T., Murawski, M. R., Jorgensen, M., Maatouk, D. M., Resnick, J. L., Li, E., & Terada, N.
- Affiliations
- University of Florida Health (US)
- Harvard University (US)
- Venue
- STEM CELLS
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-10
- Volume
- 23
- Issue
- 9
- Pages
- 1314-1323
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W1966377847
- Cited by
- 89
- References
- 46
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 3
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 59699, R01DK059699)
- National Center for Research Resources (R21RR017001, RR 17001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- adenine nucleotide translocase, DNA methylation, transcriptional silencing, mouse embryonic stem cells, stem cell differentiation, germ cells, primordial germ cells, de novo DNA methyltransferases, DNMT3A, DNMT3B, decitabine, testis, pluripotency, cis-regulatory elements
- MeSH terms
- DNA Methyltransferase 3A, DNA Methyltransferase 3B, Mitochondrial ADP, ATP Translocases, Animals, Base Sequence, Cell Differentiation, DNA (Cytosine-5-)-Methyltransferases, Embryo, Mammalian, Gene Expression Regulation, Male, Molecular Sequence Data, Promoter Regions, Genetic, RNA, Messenger, Spermatozoa, Stem Cells, Testis, DNA Methylation, Gene Silencing, Mice
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