Differential sensitivities of transcription factor target genes underlie cell type-specific gene expression profiles.
Changes in transcription factor levels and activities dictate developmental fate. Such a change might affect the full ensemble of target genes for a factor or only uniquely sensitive targets. We investigated the relationship among activity of the hematopoietic transcription factor GATA-1, chromatin occupancy, and target gene sensitivity. Graded activation of GATA-1 in GATA-1-null cells revealed high-, intermediate-, and low-sensitivity targets. GATA-1 activity requirements for occupancy and transcription often correlated. A GATA-1 amino-terminal deletion mutant severely deregulated the low-sensitivity gene Tac-2. Thus, cells expressing different levels of a cell type-specific activator can have qualitatively distinct target gene expression patterns, and factor mutations preferentially deregulate low-sensitivity genes. Unlike other target genes, GATA-1-mediated Tac-2 regulation was bimodal, with activation followed by repression, and the coregulator Friend of GATA-1 (FOG-1) selectively mediated repression. A GATA-1 mutant defective in FOG-1 binding occupied a Tac-2 regulatory region at levels higher than wild-type GATA-1, whereas FOG-1 facilitated chromatin occupancy at a distinct target site. These results indicate that FOG-1 is a determinant of GATA factor target gene sensitivity by either facilitating or opposing chromatin occupancy.
Johnson
Kirby D
KD
Molecular and Cellular Pharmacology Program, Department of Pharmacology, University of Wisconsin School of Medicine, 383 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706, USA.
Kim
Shin-Il
SI
Bresnick
Emery H
EH
D002460:Cell Line; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D015287:Neurokinin B / Q000235:genetics; D009928:Organ Specificity; D011485:Protein Binding
D050982:GATA1 Transcription Factor; D015287:Neurokinin B