The Drosophila Nab2 RNA binding protein inhibits m6A methylation and male-specific splicing of Sex lethal transcript in female neuronal tissue
Binta Jalloh,
Carly L Lancaster,
J Christopher Rounds,
Brianna E Brown,
Sara W Leung,
Ayan Banerjee,
Derrick J Morton,
Rick S Bienkowski,
Milo B Fasken,
Isaac J Kremsky,
Matthew Tegowski,
Kate Meyer,
Anita Corbett,
Ken Moberg
Affiliations
Binta Jalloh
Department of Biology, Emory University, Atlanta, United States; Department of Cell Biology Emory University School of Medicine, Atlanta, United States; Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, United States
Carly L Lancaster
Department of Biology, Emory University, Atlanta, United States; Department of Cell Biology Emory University School of Medicine, Atlanta, United States; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University, Atlanta, United States
Department of Biology, Emory University, Atlanta, United States; Department of Cell Biology Emory University School of Medicine, Atlanta, United States; Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, United States
Brianna E Brown
Department of Biology, Emory University, Atlanta, United States; Department of Cell Biology Emory University School of Medicine, Atlanta, United States
Sara W Leung
Department of Biology, Emory University, Atlanta, United States
Department of Biology, Emory University, Atlanta, United States
Derrick J Morton
Department of Biology, Emory University, Atlanta, United States; Emory Institutional Research and Academic Career Development Award (IRACDA), Fellowships in Research and Science Teaching (FIRST) Postdoctoral Fellowship, Atlanta, United States
Rick S Bienkowski
Department of Biology, Emory University, Atlanta, United States; Department of Cell Biology Emory University School of Medicine, Atlanta, United States; Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, United States
Department of Biology, Emory University, Atlanta, United States
Isaac J Kremsky
Department of Biology, Emory University, Atlanta, United States
Matthew Tegowski
Department of Biochemistry, Duke University School of Medicine, Durham, United States
Kate Meyer
Department of Biochemistry, Duke University School of Medicine, Durham, United States; Department of Neurobiology, Duke University School of Medicine, Durham, United States
The Drosophila polyadenosine RNA binding protein Nab2, which is orthologous to a human protein lost in a form of inherited intellectual disability, controls adult locomotion, axon projection, dendritic arborization, and memory through a largely undefined set of target RNAs. Here, we show a specific role for Nab2 in regulating splicing of ~150 exons/introns in the head transcriptome and focus on retention of a male-specific exon in the sex determination factor Sex-lethal (Sxl) that is enriched in female neurons. Previous studies have revealed that this splicing event is regulated in females by N6-methyladenosine (m6A) modification by the Mettl3 complex. At a molecular level, Nab2 associates with Sxl pre-mRNA in neurons and limits Sxl m6A methylation at specific sites. In parallel, reducing expression of the Mettl3, Mettl3 complex components, or the m6A reader Ythdc1 rescues mutant phenotypes in Nab2 flies. Overall, these data identify Nab2 as an inhibitor of m6A methylation and imply significant overlap between Nab2 and Mettl3 regulated RNAs in neuronal tissue.
