RRC ID 12715
Author Huang Y, Sitwala K, Bronstein J, Sanders D, Dandekar M, Collins C, Robertson G, MacDonald J, Cezard T, Bilenky M, Thiessen N, Zhao Y, Zeng T, Hirst M, Hero A, Jones S, Hess JL.
Title Identification and characterization of Hoxa9 binding sites in hematopoietic cells.
Journal Blood
Abstract The clustered homeobox proteins play crucial roles in development, hematopoiesis, and leukemia, yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 cobind at hundreds of highly evolutionarily conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation, and transcriptional activation of a network of proto-oncogenes, including Erg, Flt3, Lmo2, Myb, and Sox4. Collectively, this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia.
Volume 119(2)
Pages 388-98
Published 2012-1-12
DOI 10.1182/blood-2011-03-341081
PII blood-2011-03-341081
PMID 22072553
PMC PMC3257007
MeSH Acetylation Animals Binding Sites Biomarkers, Tumor / genetics Biomarkers, Tumor / metabolism Blotting, Western Bone Marrow Cells / metabolism Chromatin Immunoprecipitation Enhancer Elements, Genetic Epigenomics Female Gene Expression Profiling Gene Expression Regulation, Leukemic* Hematopoiesis / physiology* Homeodomain Proteins / genetics* Homeodomain Proteins / metabolism* Leukemia / genetics* Leukemia / metabolism Mice Mice, Inbred C57BL Myeloid Ecotropic Viral Integration Site 1 Protein Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Oligonucleotide Array Sequence Analysis RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Transcription Factors / genetics Transcription Factors / metabolism
IF 16.601
Times Cited 77
DNA material pMFGmIL3 (RDB1442)