A new component of the N6-methyladenosinemethyltransferase complex and Drosophila sex determination pathway
N6-methyladenosine (m6A), the most common internal modification in eukaryotic mRNA, regulates various aspects of RNA metabolism and is involved in numerous key biological processes. In Drosophila, m6A is specifically required for sex determination by modifying the pre-mRNA of Sex-lethal (Sxl), the master sex-determining gene, and facilitating its alternative splicing.
m6A is installed by a large methyltransferase complex called the m6A “writer”. The known writer complex subunits include METTL3, METTL14, WTAP/Fl(2)d, VIRMA/Vir, and Rbm15/Nito. Since mutants for these genes show unambiguous sex transformation phenotypes, Drosophila sex determination provides a unique system to screen for new components in the m6A pathway.
Using this system, the research groups led by Dr. YAN Dong at Shanghai Institute of Plant Physiology and Ecology of Chinese Academy of Sciences (CAS), together with Dr. Norbert Perrimon at Harvard Medical School, Howard Hughes Medical Institute, identified and characterized a new component of the Drosophila sex determination pathway and RNA m6A methyltransferase complex. The findings were published online in PNAS.
By mass spectrometry, the researchers identified one protein, CG7358, which interacts with known m6A writer components. As CG7358 has not been studied before, they renamed it Xiong (Xio, Chinese character for maleness) since its loss of function shows female-to-male transformation phenotype. xio encodes a conserved ubiquitous nuclear protein and it colocalizes and interacts with all previously known m6A writer complex subunits.
Loss of xio is associated with phenotypes that resemble other m6A factors, such as sexual transformations, Sxl splicing defect, held-out wings, flightless flies, and reduction of m6A levels. Thus, Xio encodes a member of the m6A methyltransferase complex involved in mRNA modification. Since its ortholog ZC3H13 also associates with several m6A writer factors, the function of Xio in the m6A pathway is likely evolutionarily conserved.
This work was supported by National Natural Science Foundation of China, Shanghai Pujiang Program and CAS.
Figure: (A) Knockdown of xio transforms female flies to male-like. (B) A model of the m6A writer complex comprised of six core components. (Image by Dr. Dong Yan)
Dr. Dong Yan, Professor
Key Laboratory of Insect Developmental and Evolutionary Biology
CAS Center for Excellence in Molecular Plant Sciences/Shanghai Institute of Plant Physiology and Ecology (SIPPE)
Chinese Academy of Sciences