Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Christina M
CM
Hughes
Orit
O
Rozenblatt-Rosen
Thomas A
TA
Milne
Terry D
TD
Copeland
Stuart S
SS
Levine
Jeffrey C
JC
Lee
D Neil
DN
Hayes
Kalai Selvi
KS
Shanmugam
Arindam
A
Bhattacharjee
Christine A
CA
Biondi
Graham F
GF
Kay
Nicholas K
NK
Hayward
Jay L
JL
Hess
Matthew
M
Meyerson
D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins; D005347:Fibroblasts / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011496:Protein Methyltransferases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
D002843:Chromatin; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C063460:Trl protein, Drosophila; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase