Control of CD4 gene expression: connecting signals to outcomes in T cell development

Sarafova, Sophia D.; Siu, Gerald

doi:10.1590/s0100-879x1999000700001

Cited by 6 publications

(7 citation statements)

References 55 publications

(88 reference statements)

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“…The S2/Pro mutant promoter was tested for function in transient transfection reporter assays in the CD4 SP T H clone D10. As we and others have reported earlier, the unmutated CD4 promoter functions at high levels in activated T H cells (28,35,37,39,44), whereas site-specific mutations of the c-Myb consensus sequence within the P1 promoter functional site (the MX mutation) lead to significant decreases in promoter activity (28,44) (Fig. 6A).…”

Section: Context Dependence Of C-myb Functionsupporting

confidence: 76%

Negative Regulation of CD4 Gene Expression by a HES-1–c-Myb Complex

Allen

Kim

Sarafova

et al. 2001

Molecular and Cellular Biology

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Expression of the CD4 gene is tightly controlled throughout thymopoiesis. The downregulation of CD4 gene expression in CD4؊ CD8 ؊ and CD4 ؊ CD8 ؉ T lymphocytes is controlled by a transcriptional silencer located in the first intron of the CD4 locus. Here, we determine that the c-Myb transcription factor binds to a functional site in the CD4 silencer. As c-Myb is also required for CD4 promoter function, these data indicate that depending on the context, c-Myb plays both positive and negative roles in the control of CD4 gene expression. Interestingly, a second CD4 silencer-binding factor, HES-1, binds to c-Myb in vivo and induces it to become a transcriptional repressor. We propose that the recruitment of HES-1 and c-Myb to the silencer leads to the formation of a multifactor complex that induces silencer function and repression of CD4 gene expression.

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Section: Context Dependence Of C-myb Functionsupporting

confidence: 76%

Negative Regulation of CD4 Gene Expression by a HES-1–c-Myb Complex

Allen

Kim

Sarafova

et al. 2001

Molecular and Cellular Biology

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“…Transcription factor sites in the minimal murine Cd4 promoter are involved in the control of developmental expression of Cd4 in mice, and expression of both the murine Cd4 and the human CD4 receptors in immature thymocytes are influenced by upstream and downstream enhancer and silencer sequences [7,8]. CD4/Cd4 transcription in mature T cells is mainly regulated by the promoter region [7][8][9] and less markedly by regulatory sites outside the promoter [7,8]. The CD4 promoter is constitutively active in CD4 þ Jurkat cells [9,12].…”

Section: Discussionmentioning

confidence: 99%

“…CD4-1188(TTTTC) [5][6][7][8][9][10][11][12][13][14] assay. Two hundred and sixteen families previously genotyped [14] for this polymorphism comprised the TDT analysis material for the VNTR.…”

Section: Methodsmentioning

confidence: 99%

“…Inhibition of CD4-MHC class II interaction severely impairs the T-cell response to antigen exposure [5], and low CD4 cell-surface expression on Th lymphocytes results in impaired TCR response to low-level antigenic stimulation [6]. The CD4 promoter seems to be the major regulatory region for CD4 transcription in the mature Th cell [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Identification of a Type 1 Diabetes‐Associated CD4 Promoter Haplotype with High Constitutive Activity

et al. 2004

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CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4 þ T cells. We previously found linkage between a CD4-1188(TTTTC) 5À14 promoter polymorphism and T1DM. In the present study, we screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC) 5À14 alleles, and we observed nine CD4 promoter haplotypes, of which four are frequent. We genotyped the SNPs in 253 Danish T1DM families (1129 individuals) and found evidence for linkage and association of a CD4 (A4 -1188 T -1050 G -521 C -181 ) haplotype to T1DM. In reporter studies, we show that (1) the T1DM-associated CD4 haplotype encodes high constitutive promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP on stimulated CD4 promoter activity and the identification of a novel CD4 haplotype with high constitutive promoter activity that is linked and associated with T1DM.

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“…This region has been shown to harbor important regulatory elements, the enhancer and silencer regions (Siu et al 1994;Sarafova and Siu 1999). TraFaC revealed significant conserved TF-binding sites in both of these known regulatory regions shown as multiple peaks on the Regulogram.…”

Section: Cd4mentioning

confidence: 99%

Detection and Visualization of Compositionally Similar cis-Regulatory Element Clusters in Orthologous and Coordinately Controlled Genes

Jegga

Sherwood²,

Carman³

et al. 2002

Genome Res.

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Evolutionarily conserved noncoding genomic sequences represent a potentially rich source for the discovery of gene regulatory regions. However, detecting and visualizing compositionally similar cis-element clusters in the context of conserved sequences is challenging. We have explored potential solutions and developed an algorithm and visualization method that combines the results of conserved sequence analyses (BLASTZ) with those of transcription factor binding site analyses (MatInspector) (http://trafac.chmcc.org). We define hits as the density of co-occurring cis-element transcription factor (TF)-binding sites measured within a 200-bp moving average window through phylogenetically conserved regions. The results are depicted as a Regulogram, in which the hit count is plotted as a function of position within each of the two genomic regions of the aligned orthologs. Within a high-scoring region, the relative arrangement of shared cis-elements within compositionally similar TF-binding site clusters is depicted in a Trafacgram. On the basis of analyses of several training data sets, the approach also allows for the detection of similarities in composition and relative arrangement of cis-element clusters within nonorthologous genes, promoters, and enhancers that exhibit coordinate regulatory properties. Known functional regulatory regions of nonorthologous and less-conserved orthologous genes frequently showed cis-element shuffling, demonstrating that compositional similarity can be more sensitive than sequence similarity. These results show that combining sequence similarity with cis-element compositional similarity provides a powerful aid for the identification of potential control regions.In higher multicellular organisms, cell-type-specific nuclear machinery has an uncanny ability to direct precise patterns of gene expression through the recognition of arrays of ciselements specified by primary DNA sequence lying in the context of higher-order chromatin structure. Computationally, however, we have little ability to identify cis-regulatory regions from primary sequence and even less ability to predict cellular compartments into which expression is specified. Improved ability to do so will advance our understanding of eukaryotic gene regulatory mechanisms, facilitate improved annotation of the genome, and provide insight into the potential effects of sequence polymorphisms on gene expression patterns. Moreover, improved understanding of cis-element clusters present in coordinately regulated gene groups may allow for the prediction of gene regulatory network behaviors during development, homeostasis, and disease. To exploit the potential power of conserved cis-element clusters to contribute to our understanding of eukaryotic gene regulation, it is critical to create database resources from multiple sequence analysis methods on the basis of both phylogenetic conservation and known binding-site matches that can be mined for patterns that correlate with experimentally gathered expression profile data. As shown by man...

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Control of CD4 gene expression: connecting signals to outcomes in T cell development

Cited by 6 publications

References 55 publications

Negative Regulation of CD4 Gene Expression by a HES-1–c-Myb Complex

Negative Regulation of CD4 Gene Expression by a HES-1–c-Myb Complex

Identification of a Type 1 Diabetes‐Associated CD4 Promoter Haplotype with High Constitutive Activity

Detection and Visualization of Compositionally Similar cis-Regulatory Element Clusters in Orthologous and Coordinately Controlled Genes

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