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Monday, January 18, 2010

Epigenetic Regulation of bases in DNA

The Human Genome project supposedly mapped human DNA. Now, we know with high probabilty, there are at least two additional bases. This is further complicated by the composition of DNA being dynamically regulated by epigenetic factors. This appears to be of importance in brain, stem, cancer and other types yet to be determined. How can one have a theory of evolution when the whole basis of genetics is in question. Isn't it great living in the second decade of the 21st century? Epigenetics, Graphene and BECs do it for me!
These papers give the gist of it:

Mamta Tahiliani,1 Kian Peng Koh,1 Yinghua Shen,2 William A. Pastor,1 Hozefa Bandukwala,1 Yevgeny Brudno,2 Suneet Agarwal,3 Lakshminarayan M. Iyer,4 David R. Liu,2,* L. Aravind,4,* Anjana Rao1,*
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.

The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain
Skirmantas Kriaucionis and Nathaniel Heintz*

Despite the importance of epigenetic regulation in neurological disorders, little is known about neuronal chromatin. Cerebellar Purkinje neurons have large and euchromatic nuclei, whereas granule cell nuclei are small and have a more typical heterochromatin distribution. While comparing the abundance of 5-methylcytosine in Purkinje and granule cell nuclei, we detected the presence of an unusual DNA nucleotide. Using thin-layer chromatography, high-pressure liquid chromatography, and mass spectrometry, we identified the nucleotide as 5-hydroxymethyl-2'-deoxycytidine (hmdC). hmdC constitutes 0.6% of total nucleotides in Purkinje cells, 0.2% in granule cells, and is not present in cancer cell lines. hmdC is a constituent of nuclear DNA that is highly abundant in the brain, suggesting a role in epigenetic control of neuronal function.

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