title: Integrated genome-wide chromatin occupancy and expression analyses identify key myeloid pro-differentiation transcription factors repressed by Myb.
abstract: To gain insight into the mechanisms by which the Myb transcription factor controls normal hematopoiesis and particularly, how it contributes to leukemogenesis, we mapped the genome-wide occupancy of Myb by chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) in ERMYB myeloid progenitor cells. By integrating the genome occupancy data with whole genome expression profiling data, we identified a Myb-regulated transcriptional program. Gene signatures for leukemia stem cells, normal hematopoietic stem/progenitor cells and myeloid development were overrepresented in 2368 Myb regulated genes. Of these, Myb bound directly near or within 793 genes. Myb directly activates some genes known critical in maintaining hematopoietic stem cells, such as Gfi1 and Cited2. Importantly, we also show that, despite being usually considered as a transactivator, Myb also functions to repress approximately half of its direct targets, including several key regulators of myeloid differentiation, such as Sfpi1 (also known as Pu.1), Runx1, Junb and Cebpb. Furthermore, our results demonstrate that interaction with p300, an established coactivator for Myb, is unexpectedly required for Myb-mediated transcriptional repression. We propose that the repression of the above mentioned key pro-differentiation factors may contribute essentially to Myb's ability to suppress differentiation and promote self-renewal, thus maintaining progenitor cells in an undifferentiated state and promoting leukemic transformation.
authors.affiliation: The University of Queensland Diamantina Institute, Brisbane, Queensland 4102, Australia.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Glazov
authors.forename: Diwakar R
authors.initials: DR
authors.lastname: Pattabiraman
authors.forename: Faisal
authors.initials: F
authors.lastname: Al-Owaidi
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gonda
mesh_terms: D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D023281:Genomics; D006657:Histones / Q000378:metabolism; D007938:Leukemia / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D038042:Myelopoiesis / Q000235:genetics*; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D002843:Chromatin; D006657:Histones; D020598:Proto-Oncogene Proteins c-myb; D012097:Repressor Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor