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Distinct modes of gene regulation by a cell-specific transcriptional activator.

ABSTRACT: 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.

SUBMITTER: Sengupta T

PROVIDER: S-EPMC2657397 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Distinct modes of gene regulation by a cell-specific transcriptional activator.

Sengupta Tanushri T Cohet Nathalie N Morlé François F Bieker James J JJ

Proceedings of the National Academy of Sciences of the United States of America 20090227 11

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 ac ...[more]

PMID: 19251649

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Project description:?-Synuclein is a member of the synucleins family of small proteins, which consists of three members:?, ?- and ?-synuclein. ?-Synuclein is abnormally expressed in a high percentage of advanced and metastatic tumors, but not in normal or benign tissues. Furthermore, ?-synuclein expression is strongly correlated with disease progression, and can stimulate proliferation, induce invasion and metastasis of cancer cells. ?-Synuclein transcription is regulated basically through the binding of AP-1 to specific sequences in intron 1. Here we show that ?-synuclein expression may be also regulated by micro RNAs (miRs) on post-transcriptional level. According to prediction by several methods, the 3'-untranslated region (UTR) of ?-synuclein gene contains targets for miRs. Insertion of ?-synuclein 3'-UTR downstream of the reporter luciferase (LUC) gene causes a 51% reduction of LUC activity after transfection into SKBR3 and Y79 cells, confirming the presence of efficient targets for miRs in this fragment. Expression of miR-4437 and miR-4674 for which putative targets in 3'-UTR were predicted caused a 61.2% and 60.1% reduction of endogenous ?-synuclein expression confirming their role in gene expression regulation. On the other hand, in cells overexpressing ?-synuclein no significant effect of miRs on ?-synuclein expression was found suggesting that miRs exert their regulatory effect only at low or moderate, but not at high level of ?-synuclein expression. Elevated level of ?-synuclein differentially changes the level of several miRs expression, upregulating the level of some miRs and downregulating the level of others. Three miRs upregulated as a result of ?-synuclein overexpression, i.e., miR-885-3p, miR-138 and miR-497 have putative targets in 3'-UTR of the ?-synuclein gene. Some of miRs differentially regulated by ?-synuclein may modulate signaling pathways and cancer related gene expression. This study demonstrates that miRs might provide cell-specific regulation of ?-synuclein expression and set the stage to further evaluate their role in pathophysiological processes.

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Distinct modes of gene regulation by a cell-specific transcriptional activator.

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Distinct modes of gene regulation by a cell-specific transcriptional activator.

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