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

Abstract

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-...

Characterization of the Human Endothelial Nitric-oxide Synthase Promoter

“…Functional interactions between MAZ and Sp1 occur in a number of genes, including c-myc (33,40). In the case of CD4, enhancer activity during development is critically dependent upon MAZ and an Ets consensus site that binds Elf-1 (51,52). The functional contributions of MAZ are complex considering that not only is MAZ necessary for efficient initiation and transcriptional elongation of c-myc P2 promoter transcripts, through the ME1a1 site in the P2 promoter, but MAZ and ME1a1-like binding sites are also involved in the transcriptional pausing/attenuation of the c-myc gene, and also the human complement C2 gene (39).…”

“…Elf-1 is a transcription factor previously implicated in the inducible activation of genes in mature T cells. For example, Elf-1 participates in the inducible regulation of CD4, granulocyte-macrophage colony-stimulating factor, and interleukin-2 receptor ␣ chain (IL-2R␣) following T cell activation (51,66). Elf-1 plays a role in the developmental regulation of the terminal transferase gene in early lymphocyte development (67).…”

“…An important facet of MAZ function is the participation of partner proteins. For instance, enhancer activity of the CD4 gene is critically dependent upon MAZ and an Ets consensus site that binds Elf-1 (51,52). Functional interactions between MAZ and Sp1 occur with a number of genes, including the adenovirus major late and the TATA-less serotonin 1a receptor promoters (33).…”

Characterization of NERF, a Novel Transcription Factor Related to the Ets Factor ELF-1

“…Thus, many B-and T-cell-specific genes contain functionally relevant binding sites for ets factors, including immunoglobulin (Ig) heavy and light chains; lck; blk; lyn; terminal deoxynucleotidyltransferase (TdT); mb-1; B29; interleukin-2 (IL-2); IL-2 receptor ␣ and ␤; CD3; CD4; and T-cell receptor ␣, ␤, and ␦ (4, 20, 21, 28, 35, 49, 50, 53, 60, 63, 81, 95). ELF-1 is a member of the Ets family and was originally viewed as a T-cell-specific transcription factor (36, 89) regulating the expression of IL-2, IL-2 receptor ␣, granulocyte-macrophage colony-stimulating factor, IL-3, CD4, human immunodeficiency virus type 2 (HIV-2), and human T-cell leukemia virus type 1 (HTLV-1) (14,27,38,49,50,63,86,95). We have recently demonstrated that ELF-1 is highly expressed in B cells, being involved in the regulation of a whole set of genes in those cells, including the IgH, blk, lyn, TdT, B29, lck, and mb-1 genes (4).…”

The Epigenetic Landscape of Lineage Choice: Lessons From the Heritability of Cd4 and Cd8 Expression

“…DHS mapping revealed several putative regulatory elements in the locus (Adlam and Siu, 2003;Sands and Nikolic-Zugic, 1992;Sawada and Littman, 1991), and eventually led to the identification of three enhancers: the distal (E4 D ) and proximal enhancers (E4 P ) at ~24kb and ~13kb upstream of the Cd4 TSS, respectively, and the thymocyte enhancer (E4 T ) at ~36 kb downstream (Adlam and Siu, 2003;Sawada and Littman, 1991;Wurster et al, 1994) (Reviewed in detail by (Taniuchi et al, 2004)). In combination with the Cd4 promoter, E4 P drives T cell specific transgene expression in multiple mouse lines (Blum et al, 1993;Hanna et al, 1994;Killeen et al, 1993).…”