Jung-Hyun Kim,1 Melody C. Baddoo,2 Eun Young Park,1 Joshua K. Stone,1 Hyeonsoo Park,3 Thomas W. Butler,1 Gang Huang,4,5 Xiaomei Yan,4,5 Florencia Pauli-Behn,6 Richard M. Myers,6 Ming Tan,1 Erik K. Flemington,2 Ssang-Taek Lim,3 and Eun-Young Erin Ahn1,3,*
1Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
2Tulane Cancer Center, Tulane University, New Orleans, LA 70112, USA
3Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
4Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
5Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
6HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
*Correspondence : Eun-Young Erin Ahn
Summary
Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia.