TY - JOUR
T1 - Distinct modes of gene regulation by a cell-specific transcriptional activator
AU - Sengupta, Tanushri
AU - Cohet, Nathalie
AU - Morlé, François
AU - Bieker, James J.
PY - 2009/3/17
Y1 - 2009/3/17
N2 - 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 β-globin. First, TAF9 functionally supports EKLF activity by enhancing its ability to activate the β-globin gene. Second, TAF9 interacts with a conserved β-globin downstream promoter element, and ablation of this interaction by β-thalassemia-causing mutations decreases its promoter activity and disables superactivation. Third, depletion of EKLF prevents recruitment of TAF9 to the β-globin promoter, whereas depletion of TAF9 drastically impairs β-promoter activity. However, a TAF9-independent mode of EKLF transcriptional activation is exhibited by the α-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.
AB - 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 β-globin. First, TAF9 functionally supports EKLF activity by enhancing its ability to activate the β-globin gene. Second, TAF9 interacts with a conserved β-globin downstream promoter element, and ablation of this interaction by β-thalassemia-causing mutations decreases its promoter activity and disables superactivation. Third, depletion of EKLF prevents recruitment of TAF9 to the β-globin promoter, whereas depletion of TAF9 drastically impairs β-promoter activity. However, a TAF9-independent mode of EKLF transcriptional activation is exhibited by the α-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.
UR - http://www.scopus.com/inward/record.url?scp=63149139035&partnerID=8YFLogxK
U2 - 10.1073/pnas.0808347106
DO - 10.1073/pnas.0808347106
M3 - Article
C2 - 19251649
AN - SCOPUS:63149139035
SN - 0027-8424
VL - 106
SP - 4213
EP - 4218
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -