Mammalian RNA Demethylase ALKBH5 Impacts RNA Metabolism and Mouse Fertility
N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. A collaborative study, conducted in the laboratory of prof. YANG Yungui from Beijing Institute of Genomics (BIG) in collaboration with prof. HE Chuan from University of Chicago and prof. KLUNGLAND Arne from University of Oslo, revealed that the dioxygenase ALKBH5 is the second enzyme oxidatively demethylating N6-Methyladenosine (m6A) in mammalian RNAs.
They identified ALKBH5 as another mammalian demethylase that oxidatively reverses m6A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m6A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, they have further identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis- related mRNAs involved in the p53 functional interaction network.
The 5-meC modification of DNA is known to play dynamic roles in epigenetic regulation in mammalian cells. Discovery and characterization of the first two RNA demethylases FTO and ALKBH5 indicates that, similar to the epigenetic regulatory role of DNA methylation, the reversible m6A modification in mammalian RNAs (particularly mRNAs) represents another novel epigenetic marker with potential broad roles in fundamental biological processes including adipogenesis, spermatogenesis, development, carcinogenesis, stem cell renewal and other as yet uncharacterized processes.
This study was published online in Molecular Cell on November 21, 2012.
Reversiable N6-methyl-adenosine (m6A) in RNA with a Novel Epigenetic Function (Image by Professor YANG Yungui)
Paper link: http://www.sciencedirect.com/science/article/pii/S1097276512008921
Contact: Dr WU Yongsheng
Email: wuysh@big.ac.cn
