Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification
Shinsuke Ito,Ana C. D’Alessio,Ana C. D’Alessio,Olena Taranova,Olena Taranova,Kwonho Hong,Kwonho Hong,Lawrence C. Sowers,Yi Zhang,Yi Zhang +9 more
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TLDR
It is demonstrated that all three mouse Tet proteins (Tet1, Tet2 and Tet3) can also catalyse a similar reaction, uncover the enzymatic activity of the Tet proteins, and demonstrate a role for Tet1 in ES cell maintenance and inner cell mass cell specification.Abstract:
DNA methylation is one of the best-characterized epigenetic modifications. Although the enzymes that catalyse DNA methylation have been characterized, enzymes responsible for demethylation have been elusive. A recent study indicates that the human TET1 protein could catalyse the conversion of 5-methylcytosine (5mC) of DNA to 5-hydroxymethylcytosine (5hmC), raising the possibility that DNA demethylation may be a Tet1-mediated process. Here we extend this study by demonstrating that all three mouse Tet proteins (Tet1, Tet2 and Tet3) can also catalyse a similar reaction. Tet1 has an important role in mouse embryonic stem (ES) cell maintenance through maintaining the expression of Nanog in ES cells. Downregulation of Nanog via Tet1 knockdown correlates with methylation of the Nanog promoter, supporting a role for Tet1 in regulating DNA methylation status. Furthermore, knockdown of Tet1 in pre-implantation embryos results in a bias towards trophectoderm differentiation. Thus, our studies not only uncover the enzymatic activity of the Tet proteins, but also demonstrate a role for Tet1 in ES cell maintenance and inner cell mass cell specification.read more
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Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
Shinsuke Ito,Li Shen,Qing Dai,Susan C. Wu,Leonard B. Collins,James A. Swenberg,Chuan He,Yi Zhang +7 more
TL;DR: This study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation, and identifies two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins.
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CpG Islands and the Regulation of Transcription
Aimee M. Deaton,Adrian Bird +1 more
TL;DR: Vertebrate CpG islands are generically equipped to influence local chromatin structure and simplify regulation of gene activity.
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DNA methylation: roles in mammalian development
TL;DR: Key concepts in the function of DNA methylation in mammals are discussed, stemming from more than two decades of research, including many recent studies that have elucidated when and whereDNA methylation has a regulatory role in the genome.
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Epigenetic modifications and human disease
Anna Portela,Manel Esteller +1 more
TL;DR: A comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research.
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DNA Methylation and Its Basic Function
Lisa D Moore,Thuc Le,Guoping Fan +2 more
TL;DR: The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.
References
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DNA methylation patterns and epigenetic memory
TL;DR: The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development.
Journal ArticleDOI
Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
Mamta Tahiliani,Kian Peng Koh,Yinghua Shen,William A. Pastor,Hozefa S. Bandukwala,Yevgeny Brudno,Suneet Agarwal,Lakshminarayan M. Iyer,David R. Liu,L. Aravind,Anjana Rao +10 more
TL;DR: It is shown here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro.
Journal ArticleDOI
Linking DNA methylation and histone modification: patterns and paradigms
Howard Cedar,Yehudit Bergman +1 more
TL;DR: Relationships between DNA methylation and histone modification have implications for understanding normal development as well as somatic cell reprogramming and tumorigenesis.
Journal ArticleDOI
High sensitivity mapping of methylated cytosines.
TL;DR: A genomic sequencing technique which is capable of detecting every methylated cytosine on both strands of any target sequence, using DNA isolated from fewer than 100 cells is developed.
Journal ArticleDOI
Nanog safeguards pluripotency and mediates germline development.
Ian Chambers,José C. R. Silva,Douglas Colby,Jennifer Nichols,Jennifer Nichols,Bianca Nijmeijer,Morag Robertson,Jan Vrána,Kenneth Jones,Kenneth Jones,Lars Grotewold,Austin Smith +11 more
TL;DR: By genetic deletion, it is shown that, although they are prone to differentiate, embryonic stem cells can self-renew indefinitely in the permanent absence of Nanog, and it is surmised that Nanog stabilizes embryonicstem cells in culture by resisting or reversing alternative gene expression states.