DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show 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. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference–mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.

/pdf/conversion-of-5-methylcytosine-to-5-hydroxymethylcytosine-in-30xwwwwmf6.pdf

Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1

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“Bioinformatics” 특집을 내면서

Hypoxia-Inducible Factors in Physiology and Medicine

http://basicmed.med.ncku.edu.tw/admin/up_img/1007-2.pdf

Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases

ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility

Beyond established roles in collagen biosynthesis, hypoxic signaling and fatty acid metabolism, recent reports have now revealed roles for human 2-oxoglutarate-dependent oxygenases in histone and nucleic acid demethylation and in signaling protein hydroxylation. The emerging role of these oxygenases in enabling a multiplicity of histone modifications has some analogy with their role in enabling structural diversity in secondary metabolism.

Expanding chemical biology of 2-oxoglutarate oxygenases

Codon optimization can improve expression of human genes in Escherichia coli: A multi-gene study

The transcription factor HIF (hypoxia-inducible factor) mediates a highly pleiotrophic response to hypoxia. Many recent studies have focused on defining the extent of this transcriptional response. In the present study we have analysed regulation by hypoxia among transcripts encoding human Fe(II)- and 2-oxoglutarate-dependent oxygenases. Our results show that many of these genes are regulated by hypoxia and define two groups of histone demethylases as new classes of hypoxia-regulated genes. Patterns of induction were consistent across a range of cell lines with JMJD1A (where JMJD is Jumonji-domain containing) and JMJD2B demonstrating robust, and JMJD2C more modest, up-regulation by hypoxia. Functional genetic and chromatin immunoprecipitation studies demonstrated the importance of HIF-1alpha in mediating these responses. Given the importance of histone methylation status in defining patterns of gene expression under different physiological and pathophysiological conditions, these findings predict a role for the HIF system in epigenetic regulation.

/pdf/regulation-of-jumonji-domain-containing-histone-demethylases-5fb1a6fzfw.pdf

Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha.

https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(10)00134-9.pdf

Christoph Loenarz

Papers

Expanding chemical biology of 2-oxoglutarate oxygenases

Codon optimization can improve expression of human genes in Escherichia coli: A multi-gene study

Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1alpha.

Physiological and biochemical aspects of hydroxylations and demethylations catalyzed by human 2-oxoglutarate oxygenases

Structural studies on human 2-oxoglutarate dependent oxygenases