Menin Associates with a Trithorax Family Histone Methyltransferase Complex and with the Hoxc8 Locus

Abstract

The cellular function of the menin tumor suppressor protein, product of the MEN1 gene mutated in familial multiple endocrine neoplasia type 1, has not been defined. We now show that menin is associated with a histone methyltransferase complex containing two trithorax family proteins, MLL2 and Ash2L, and other homologs of the yeast Set1 assembly. This menin-associated complex methylates histone H3 on lysine 4. A subset of tumor-derived menin mutants lacks the associated histone methyltransferase activity. In addition, menin is associated with RNA polymerase II whose large subunit carboxyl-terminal domain is phosphorylated on Ser 5. Men1 knockout embryos and cells show decreased expression of the homeobox genes Hoxc6 and Hoxc8. Chromatin immunoprecipitation experiments reveal that menin is bound to the Hoxc8 locus. These results suggest that menin activates the transcription of differentiation-regulating genes by covalent histone modification, and that this activity is related to tumor suppression by MEN1.

Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-κB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes

“…Thus, overexpressed p52 and Hut-78 induce MMP9 expression by tethering a H3K4 HMT complex. Whereas one multi-subunit complex (referred to as COMPASS and Set1 complex) that includes the Drosophila trithorax-related protein Set1 has been shown to trigger the mono-, di-and trimethylation of histone H3K4 in yeast (Briggs et al, 2001;Miller et al, 2001;Nagy et al, 2002;Noma and Grewal, 2002), multiple complexes harbouring robust H3K4 HMT activities have been isolated in mammalian cells and all of them contained one or two SET domain-containing homologues of yeast Set1 (Hughes et al, 2004;Glaser et al, 2006). As those distinct Set-1-like human H3K4 HMT complexes also share common subunits such as ASH2L, RBBP5 and WDR5, we determined whether those proteins interact with p52 by coimmunoprecipitation experiments.…”

Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression

“…Recent progress in studying the function of menin suggests that menin has diverse functions, including regulation of gene transcription (Agarwal et al, 1999;Kaji et al, 2001;Lin and Elledge, 2003;Hughes et al, 2004;La et al, 2004a;Schnepp et al, 2004b), cell proliferation (Kim et al, 1999;Kaji et al, 2001;La et al, 2004b;Ratineau et al, 2004;Schnepp et al, 2004a), apoptosis (Sayo et al, 2002;Schnepp et al, 2004b) and genome stability (Scappaticci et al, 1992;Jin et al, 2003;Busygina et al, 2004). Menin is primarily a nuclear protein and possesses two classic nuclear localization signals, NLS1 and NLS2 (Guru et al, 1998).…”

“…Typical NLSs consist of multiple positively charged amino-acid residues (Moroianu, 1999), and these basic residues specifically bind to a soluble transport receptor complex comprising importin a and importin b (Komeili and O'Shea, 2001), leading to translocation into the nucleus. As menin associates with chromatin and nuclear matrix (Jin et al, 2003), directly binds double-stranded DNA (dsDNA) , and regulates gene expression (Agarwal et al, 1999;Kaji et al, 2001;Lin and Elledge, 2003;Hughes et al, 2004;La et al, 2004a;Schnepp et al, 2004b), its nuclear localization should be essential for its role in regulation of gene transcription.…”

“…Menin has also been shown to induce expression of various genes including Hox genes and the proapoptotic gene caspase 8 (Hughes et al, 2004;Schnepp et al, 2004b;Yokoyama et al, 2004). Menin induces expression of Hoxc8 and Hoxa9 genes through interacting with histone methyltransfereases, which are crucial for expression of many Hox genes (Hughes et al, 2004;Yokoyama et al, 2004).…”

“…Menin induces expression of Hoxc8 and Hoxa9 genes through interacting with histone methyltransfereases, which are crucial for expression of many Hox genes (Hughes et al, 2004;Yokoyama et al, 2004). The menin NLSs are essential for binding to dsDNA , but it is not clear whether these NLSs are required for coordinating induction and repression of various menin target genes.…”