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

Jung Hyun Kim, Melody C. Baddoo, Eun Young Park, Joshua K. Stone, Hyeonsoo Park, Thomas W. Butler, Gang Huang, Xiaomei Yan, Florencia Pauli-Behn, Richard M. Myers, Ming Tan, Erik K. Flemington, Ssang Taek Lim, Eun Young Erin Ahn

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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. Kim et al. demonstrate that SON and its splice variants control MLL complex-mediated transcriptional initiation. Full-length SON binds menin and inhibits MLL complex assembly, decreasing H3K4me3. Short, alternatively spliced SON isoforms are upregulated in acute myeloid leukemia and antagonize full-length SON function.

Original languageEnglish (US)
Pages (from-to)859-873
Number of pages15
JournalMolecular Cell
Volume61
Issue number6
DOIs
StatePublished - Mar 17 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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