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

Abstract

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.

Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair

“…In MLL-rearranged AML, certain MLL fusion proteins display enhanced activity to promote gene transcription by recruiting a transcriptional activation complex known as P-TEFb that consists of CDK9 and cyclin T1 [47, 48]. The leukemia-driving activity of MLL fusion proteins relies on their interaction with menin, a protein encoded by the multiple endocrine neoplasia (MEN1) gene [49]. Menin directly binds to the N-terminal domain of MLL in virtually all MLL fusion proteins, an event that is essential for leukemic transformation [50].…”

Germline Stem Cell Heterogeneity Supports Homeostasis in Drosophila

“…CG8273 (called dSon or dsn hereafter) is highly expressed in the ovaries ( Figure S2 ). dsn is the homolog of human SON, which is involved in transcriptional repression and splicing ( Kim et al., 2016a , Lu et al., 2014 , Sun et al., 2001 ). SON had been shown to regulate self-renewal in human embryonic stem cells and mutations in SON are associated with abnormal brain development and leukemia ( Kim et al., 2016a , Kim et al., 2016b , Lu et al., 2013 , Tokita et al., 2016 ).…”

MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity

“…In addition to known interaction partners of the wild-type MLL protein, such as MEN1, DPY30, and LEDGF, it also contains several proteins whose link to AML biology have only recently been established. For instance, the protein SON interacts with MEN1 to regulate the expression of leukemia-specific genes in a MLL-dependent manner 55 . Thus, functional annotation of the core network of MLL-fusion interactors will contribute to establish novel links between MLL-fusion proteins and important cellular processes that had previously not been associated with the biology of MLL-fusion proteins, such as mRNA splicing or protein transport.…”