Cooperative Regulation of Fc Receptor γ-Chain Gene Expression by Multiple Transcription Factors, Including Sp1, GABP, and Elf-1

Abstract

The Fc receptor ␥-chain (FcR␥), which was first identified as a constituent of the high affinity IgE receptor, associates with various cell surface receptors to mediate intracellular signals. We identified three transcriptional enhancer elements in the 5 region of the human FcR␥ gene; one of the cis-elements was recognized by the transcription factor Sp-1 and another was recognized by GABP or Elf-1. The sequence of the other element was similar to a binding motif of the C/EBP family. Overexpression experiments showed that these transcription factors cooperatively activated the FcR␥ promoter. Furthermore, inactivation of the GABP-binding site by nucleotide substitutions as well as repression of GABP␣ expression by RNA interference reduced Sp1-mediated transactivation of the FcR␥ promoter, demonstrating that Sp1 and GABP synergistically activated the FcR␥ promoter. This synergistic activation was suggested to require physical interaction between the two transcription factors, because the Ets domain of GABP␣ was demonstrated to directly bind Sp1. On the other hand, GABP and Elf-1, whose recognition sequences overlapped, were shown to bind the FcR␥ gene with similar affinity in the context of chromatin, although Elf-1 exerted weaker enhancer activity for FcR␥ gene expression than did GABP. Both were thought to compete for binding to the element, because additional expression of Elf-1 in combination with Sp1 and GABP reduced FcR␥ promoter activity. Such functional and physical interactions among transcription factors involved in the cooperative regulation of FcR␥ gene expression as revealed in this study will become promising targets for medical applications against various immune diseases involving FcR␥.

Transcriptional regulation of mouse l-selectin

“…The interaction of Ets family transcription factors with Sp1 has been shown to synergistically trans-activate many genes including human CD18 [14], Tenascin-C [21], Fc receptor γ-chain [22], and interleukin-12 p40 [23]. In the mouse sell promoter, an Sp1 binding site overlaps with an Ets1 binding site.…”

Nuclear Respiratory Factor 2 Induces the Expression of Many but Not All Human Proteins Acting in Mitochondrial DNA Transcription and Replication

“…The observation that mTERF and TWINKLE mRNAs decrease similarly and yet mTERF promoter only contains two tandemly arranged sites that bind with high affinity two ␣/␤ NRF-2 monomers indicates a lack of correlation between the extent of mRNA level decrease and the number and arrangement of NRF-2 sites. It is notable that the TWINKLE promoter contains, in close proximity of the Ϫ45 NRF-2 site, a sequence recognized by Sp1, a factor that is known to physically and functionally interact with NRF-2 on several promoters (8,31). …”

Long-Range Modulation of PAG1 Expression by 8q21 Allergy Risk Variants

“…The most plausible candidate target genes are TPD52 (MIM: 604068), which is involved in B cell maturation; 6 PAG1 (MIM: 605767), involved in T and B cell activation; 7-10 and ZBTB10, a putative repressor of the Sp1 transcription factor (TF), 11 which regulates multiple immune-related genes. 12,13 We first considered the possibility that the lack of a published association between rs7009110 and the expression of nearby genes could represent a false-negative finding, arising because (1) a true association did not exceed the false discovery rate threshold in the original eQTL studies and so was not reported; and/or (2) most published eQTL studies surveyed used expression microarrays, which have incomplete coverage of gene expression patterns. To test this possibility, we analyzed RNA-seq data obtained by the Geuvadis Project 14 for lymphoblastoid cell line (LCL) samples of 373 individuals of European descent from the 1000 Genomes Project.…”