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Mol Cell. 2016 Mar 17;61(6):859-73. doi: 10.1016/j.molcel.2016.02.024.

SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes.

Author information

1
Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
2
Tulane Cancer Center, Tulane University, New Orleans, LA 70112, USA.
3
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
4
Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
5
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
6
Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA. Electronic address: eahn@health.southalabama.edu.

Abstract

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.

PMID:
26990989
PMCID:
PMC4799497
DOI:
10.1016/j.molcel.2016.02.024
[Indexed for MEDLINE]
Free PMC Article

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