Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy.
GATA factors interact with simple DNA motifs (WGATAR) to regulate critical processes, including hematopoiesis, but very few WGATAR motifs are occupied in genomes. Given the rudimentary knowledge of mechanisms underlying this restriction and how GATA factors establish genetic networks, we used ChIP-seq to define GATA-1 and GATA-2 occupancy genome-wide in erythroid cells. Coupled with genetic complementation analysis and transcriptional profiling, these studies revealed a rich collection of targets containing a characteristic binding motif of greater complexity than WGATAR. GATA factors occupied loci encoding multiple components of the Scl/TAL1 complex, a master regulator of hematopoiesis and leukemogenic target. Mechanistic analyses provided evidence for crossregulatory and autoregulatory interactions among components of this complex, including GATA-2 induction of the hematopoietic corepressor ETO-2 and an ETO-2-negative autoregulatory loop. These results establish fundamental principles underlying GATA factor mechanisms in chromatin and illustrate a complex network of considerable importance for the control of hematopoiesis.
Fujiwara
Tohru
T
University of Wisconsin School of Medicine and Public Health, Wisconsin Institutes for Medical Research, Madison, 53705, USA.
O'Geen
Henriette
H
Keles
Sunduz
S
Blahnik
Kimberly
K
Linnemann
Amelia K
AK
Kang
Yoon-A
YA
Choi
Kyunghee
K
Farnham
Peggy J
PJ
Bresnick
Emery H
EH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D050989:GATA2 Transcription Factor / Q000378:metabolism*; D020869:Gene Expression Profiling; D056426:Genetic Loci; D015894:Genome, Human / Q000235:genetics*; D006413:Hematopoietic System / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C494688:GATA1 protein, human; C494711:GATA2 protein, human; C067143:TAL1 protein, human