Genome-wide analysis of menin binding provides insights into MEN1 tumorigenesis.
Multiple endocrine neoplasia type I (MEN1) is a familial cancer syndrome characterized primarily by tumors of multiple endocrine glands. The gene for MEN1 encodes a ubiquitously expressed tumor suppressor protein called menin. Menin was recently shown to interact with several components of a trithorax family histone methyltransferase complex including ASH2, Rbbp5, WDR5, and the leukemia proto-oncoprotein MLL. To elucidate menin's role as a tumor suppressor and gain insights into the endocrine-specific tumor phenotype in MEN1, we mapped the genomic binding sites of menin, MLL1, and Rbbp5, to approximately 20,000 promoters in HeLa S3, HepG2, and pancreatic islet cells using the strategy of chromatin-immunoprecipitation coupled with microarray analysis. We found that menin, MLL1, and Rbbp5 localize to the promoters of thousands of human genes but do not always bind together. These data suggest that menin functions as a general regulator of transcription. We also found that factor occupancy generally correlates with high gene expression but that the loss of menin does not result in significant changes in most transcript levels. One exception is the developmentally programmed transcription factor, HLXB9, which is overexpressed in islets in the absence of menin. Our findings expand the realm of menin-targeted genes several hundred-fold beyond that previously described and provide potential insights to the endocrine tumor bias observed in MEN1 patients.
Scacheri
Peter C
PC
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Davis
Sean
S
Odom
Duncan T
DT
Crawford
Gregory E
GE
Perkins
Stacie
S
Halawi
Mohamad J
MJ
Agarwal
Sunita K
SK
Marx
Stephen J
SJ
Spiegel
Allen M
AM
Meltzer
Paul S
PS
Collins
Francis S
FS
D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D015894:Genome, Human; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D008957:Models, Genetic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C105373:MEN1 protein, human; C490003:MNX1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C470552:RBBP5 protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase