Sequence-Specific Binding of Human Ets-1 to the T Cell Receptor α Gene Enhancer

Ho, I‐Cheng; Bhat, Narayan K.; Gottschalk, Lisa; Lindsten, Tullia; Thompson, Craig B.; Papas, Takis S.; Leiden, Jeffrey M.

doi:10.1126/science.2237431

Cited by 218 publications

(148 citation statements)

References 31 publications

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“…4A). The choices for nucleotide substitutions were based on previous studies in which either factor binding or functional activity of the particular binding site was destroyed (3,23,24,38). These mutant enhancer fragments were subcloned into the luciferase expression vector with the minimal CD4 promoter and transiently transfected into D10 T cells, and the enhancer activity was then compared with activities unmutated enhancer constructs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Elf-1 binds to a critical element in a second CD4 enhancer.

Wurster¹,

Siu²,

Leiden³

et al. 1994

Mol. Cell. Biol.

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The coordinated expression of CD4 and CD8 during T-cell development is tightly coupled with the maturation state of the T cell. Additionally, the mutually exclusive expression of these receptors in mature T cells is representative of the functional T-cell subclasses (CD4+ helper T cells versus CD8+ cytotoxic T cells). We have studied the regulation CD4 gene transcription during T-cell development in an attempt to gain an understanding of the molecular mechanisms involved in T-cell development and differentiation. Here we present the identification of a second transcriptional enhancer in the murine CD4 locus 24 kb upstream of the CD4 promoter. This enhancer is active in mature T cells and is especially active in CD4+ helper T cells. A number of nuclear proteins bind to elements in the minimal CD4 enhancer that includes consensus sites for AP-1, Spl, Gata, and Ets transcription factor families. We find that the Ets consensus site is crucial for enhancer activity and that the recently identified Ets factor, Elf-i, which is expressed at high levels in T cells and involved in the regulation of several other T-cell-specific genes, is a dominant protein in T-cell nuclear extracts that binds to this site.T-cell development involves the differentiation of functionally immature pre-T cells into mature, antigen-reactive effector cells (reviewed in reference 61). This process includes selection events in which the maturing T-cell population is depleted of self-reactive clones and enriched for those that can recognize foreign peptides bound by self-major histocompatibility complex (MHC). The development and selection of T-cell precursors occur in the thymus and are characterized by a coordinated expression of tissue-specific genes. Some of these genes encode cell surface molecules that directly promote T-cell differentiation and selection events. Understanding the molecular mechanisms responsible for the expression of these T-cellspecific genes is a window on the process of T-cell development.The CD4 glycoprotein is one of the surface molecules that is important as a receptor in the development and function of T cells (reviewed in references 39 and 46). In mature antigenspecific T cells, CD4 is expressed only on cells that have a T-cell receptor (TCR) specific for antigen associated with class II MHC molecules, while CD8, a cell surface protein functionally similar to CD4, is expressed only on T cells that recognize antigen bound to MHC class I molecules (56). The mutually exclusive expression of CD4 and CD8 on mature T cells also corresponds to T-cell function; CD4 is expressed primarily on helper T cells, while CD8 is expressed on cytotoxic T cells. CD4 participates in antigen recognition by binding to nonpolymorphic regions of class II MHC molecules, while the T-cell antigen receptor recognizes a specific peptide antigen that is bound by the MHC molecule (7). The CD4-MHC interaction serves to increase the avidity of the T cell to the antigenpresenting cell but also induces an intracellular signaling event through the CD4-...

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Section: Resultsmentioning

confidence: 99%

Elf-1 binds to a critical element in a second CD4 enhancer.

Wurster¹,

Siu²,

Leiden³

et al. 1994

Mol. Cell. Biol.

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“…CD4 and CD8 human T cell predictors rely on synergistic relations between experimentally verified DNA-binding motifs for ETS, YY1, and factors from the CREB family. ETS-family factors are ubiquitously expressed (21) but are well known to have an important role in regulation of transcription in T cells (22,23). Members of the ETS and CREB families are known to interact (24)(25)(26).…”

Section: Resultsmentioning

confidence: 99%

DNA motifs in human and mouse proximal promoters predict tissue-specific expression

Smith

Sumazin

Xuan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

118

126

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Comprehensive identification of cis-regulatory elements is necessary for accurately reconstructing gene regulatory networks. We studied proximal promoters of human and mouse genes with differential expression across 56 terminally differentiated tissues. Using in silico techniques to discover, evaluate, and model interactions among sequence elements, we systematically identified regulatory modules that distinguish elevated from inhibited expression in the corresponding transcripts. We used these putative regulatory modules to construct a single predictive model for each of the 56 tissues. These predictors distinguish tissue-specific elevated from inhibited expression with statistical significance in 80% of the tissues (45 of 56). The predictors also reveal synergy between cis-regulatory modules and explain large-scale tissuespecific differential expression. For testis and liver, the predictors include computationally predicted motifs. For most other tissues, the predictors reveal synergy between experimentally verified motifs and indicate genes that are regulated by similar tissuespecific machinery. The identification in proximal promoters of cis-regulatory modules with tissue-specific activity lays the groundwork for complete characterization and deciphering of cis-regulatory DNA code in mammalian genomes.cis-regulatory modules ͉ transcription factor binding A major first step toward comprehensively understanding the differential control of gene expression in specific tissues and developmental stages is mapping the functional cis-regulatory modules (CRMs) (1) responsible for transcription regulation. CRMs are autonomous units of transcription programs encoded in DNA (2-4) and are largely composed of transcription factorbinding sites (TFBSs). Identification and categorization of the entire repertoire of TFBSs are among the greatest challenges in systems biology (5-7). Although CRM identification in lower eukaryotes, such as various yeast species, has been progressing rapidly (8, 9), similar efforts in vertebrates have proven to be especially difficult due to the genomic and regulatory complexity of the higher organisms (10). CRMs in vertebrate regulatory regions not only control transcription during the life of individual cells but also must orchestrate cellular communication during tissue differentiation, morphogenesis, and body-part formation (11), as well as maintain specific patterns of transcription in terminally differentiated tissues (12).Recent work to predict expression using cis-regulatory elements includes studies on yeast (6,9,13,14), identification of target genes and binding sites for specific transcription factors (15, 16), and an evaluation of the effect of TFBS quality (17) on target regulation. Bussemaker et al. (13) and Conlon et al. (14) used linear regression to fit the count of predicted cis-regulatory elements (13) or the sum of the likelihood ratios of all potential cis-regulatory elements (14) to expression intensity. Beer and Tavazoie (6) used cis-regulatory elements in promoters to s...

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“…Ets-1 and other Ets proteins participate into the transcriptional regulation of numerous genes whose products are critical for the development or the function of lymphoid cells (24)(25)(26)(27)(28)(29). Thus, inactivation of Ets-1 could lower or extinguish expression of genes whose products are components of the pre-TCR or are involved in pre-TCR function.…”

Section: Discussionmentioning

confidence: 99%

The Ets-1 transcription factor is required for complete pre-T cell receptor function and allelic exclusion at the T cell receptor β locus

Eyquem

Chemin

Fasseu

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The pre-T cell receptor (TCR) functions as a critical checkpoint during ␣␤ T cell development. Signaling through the pre-TCR controls the differentiation of immature CD4 ؊ CD8 ؊ CD25 ؉ CD44 ؊ [double-negative (DN)3] thymocytes into CD4 ؉ CD8 ؉ double-positive (DP) cells through the CD4 ؊ CD8 ؊ CD25 ؊ CD44 ؊ (DN4) stage. In addition, pre-TCR activity triggers expansion and survival of thymocytes and inhibits TCR␤ gene rearrangement through a process referred to as allelic exclusion. Whereas many proteins involved in the pre-TCR transduction cascade have been identified, little is known about the nuclear factors associated with receptor function. Here, we use gene targeting to inactivate the Ets-1 transcription factor in mice and analyze pre-TCR function in developing Ets-1-deficient (Ets-1 ؊/؊ ) thymocytes. We find that inactivation of Ets-1 impairs the development of DN3 into DP thymocytes and induces an elevated rate of cell death in the DN4 subset. This defect appears specific to the ␣␤ lineage because ␥␦ T cells maturate efficiently. Finally, the percentage of thymocytes coexpressing two different TCR␤ chains is increased in the Ets-1 ؊/؊ background and, in contrast with wild type, forced activation of pre-TCR signaling does not block endogenous TCR␤ gene rearrangement. These data identify Ets-1 as a critical transcription factor for pre-TCR functioning and for allelic exclusion at the TCR␤ locus. L ymphocytes develop from multipotent stem cells through a regulated sequence of events that controls the production of functional T, B, and natural killer cells (1). The great majority of immunocompetent T cells are generated in the thymus where their maturation can be followed by expression of specific cell-surface markers (2). The most immature thymocyte population is found within the double-negative (DN) subset of cells lacking the CD4 and CD8 coreceptors. DN cells are further subdivided into four consecutive populations; DN1 (CD44 ϩ CD25 Ϫ ), DN2 (CD44 ϩ CD25 ϩ ), DN3 (CD44 Ϫ CD25 ϩ ), and DN4 (CD44 Ϫ CD25 Ϫ ). As immature DN1 cells differentiate to the DN2 and DN3 stages, they begin to commit into the T cell lineage and start rearranging their T cell receptor (TCR) loci (3). In-frame rearrangement of the TCR␤ gene allows the production of a ␤-chain, which is expressed at the thymocyte cell surface within the pre-TCR (4). Expression of the pre-TCR activates a set of intracellular signaling pathways that allow a specific genetic program to be switched on (5-7). This program results in CD25 down-regulation, rescue of differentiating cells from apoptosis, and intense proliferation and progression to the double-positive (DP) stage (CD4 ϩ CD8 ϩ ). In addition, the function of the pre-TCR is essential to inhibit further rearrangements at the TCR␤ locus, insuring that each T cell expresses a unique ␤-chain through a process referred to as allelic exclusion. Thus, by modulating the transcription of specific genes, the pre-TCR signaling selects for DP thymocytes bearing a unique functional TCR␤ chain through a process r...

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Sequence-Specific Binding of Human Ets-1 to the T Cell Receptor α Gene Enhancer

Cited by 218 publications

References 31 publications

Elf-1 binds to a critical element in a second CD4 enhancer.

Elf-1 binds to a critical element in a second CD4 enhancer.

DNA motifs in human and mouse proximal promoters predict tissue-specific expression

The Ets-1 transcription factor is required for complete pre-T cell receptor function and allelic exclusion at the T cell receptor β locus

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