Distinct modes of gene regulation by a cell-specific transcriptional activator.
The architectural layout of a eukaryotic RNA polymerase II core promoter plays a role in general transcriptional activation. However, its role in tissue-specific expression is not known. For example, differing modes of its recognition by general transcription machinery can provide an additional layer of control within which a single tissue-restricted transcription factor may operate. Erythroid Kruppel-like factor (EKLF) is a hematopoietic-specific transcription factor that is critical for the activation of subset of erythroid genes. We find that EKLF interacts with TATA binding protein-associated factor 9 (TAF9), which leads to important consequences for expression of adult beta-globin. First, TAF9 functionally supports EKLF activity by enhancing its ability to activate the beta-globin gene. Second, TAF9 interacts with a conserved beta-globin downstream promoter element, and ablation of this interaction by beta-thalassemia-causing mutations decreases its promoter activity and disables superactivation. Third, depletion of EKLF prevents recruitment of TAF9 to the beta-globin promoter, whereas depletion of TAF9 drastically impairs beta-promoter activity. However, a TAF9-independent mode of EKLF transcriptional activation is exhibited by the alpha-hemoglobin-stabilizing protein (AHSP) gene, which does not contain a discernable downstream promoter element. In this case, TAF9 does not enhance EKLF activity and depletion of TAF9 has no effect on AHSP promoter activation. These studies demonstrate that EKLF directs different modes of tissue-specific transcriptional activation depending on the architecture of its target core promoter.
Sengupta
Tanushri
T
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Cohet
Nathalie
N
Morlé
François
F
Bieker
James J
JJ
D001798:Blood Proteins; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism / Q000502:physiology*; D018832:Molecular Chaperones; D009154:Mutation; D011401:Promoter Regions, Genetic; D035381:TATA-Binding Protein Associated Factors / Q000378:metabolism*; D014018:Tissue Distribution; D035362:Transcription Factor TFIID / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D055544:beta-Globins / Q000096:biosynthesis / Q000235:genetics; D017086:beta-Thalassemia / Q000235:genetics
C468768:AHSP protein, human; D001798:Blood Proteins; D051741:Kruppel-Like Transcription Factors; D018832:Molecular Chaperones; C106849:TAF9 protein, human; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; D055544:beta-Globins; C080774:erythroid Kruppel-like factor