HEB in the Spotlight: Transcriptional Regulation of T-Cell Specification, Commitment, and Developmental Plasticity

Figure 2

Timeline of E-protein discovery. In 1985, Ephrussi et al. identified regions in the immunoglobulin (Ig) heavy chain gene enhancer (μE1–μE5) that were occupied by unidentified DNA-binding proteins in the B-cell lines, but not in nonlymphoid cells [62]. The regions had a CANNTG consensus sequence, which was later named an E-box. In 1989, Murre et al. discovered that E-boxes in the Ig-heavy and light-chain enhancers were occupied by two novel proteins, which they named E47 and E12 [63]. These were the first E-proteins discovered, so called because they bind to the E-box sites. In 1990, the search for transcription factors that bind Ig light-chain enhancer sites (κE1–κE3) revealed a second E-protein, ITF-2A [64], later named E2-2Alt [65]. Concurrent studies by Hu et al. involved the use of the μE2 sequence to screen a cDNA library from HeLa cells, a human cell line, which led to the discovery of the third E-protein in 1992 [66]; the mouse counterpart was discovered later that year [67]. This protein was named HEB (HeLa E-box binding factor). In 1997, a splice variant of E2-2 was identified [68] and named ITF-2b (now called E2-2Can), which in contrast to E2-2Alt had an inhibitory effect on the promoter of a muscle-specific gene [69]. In 1999, Anderson et al. set out to identify transcription factors involved in T-cell specification by screening a SCID (severe combined immunodeficient)-thymocyte cDNA library. The search revealed a novel HEB clone [70], which was transcribed from the HEB locus from its own transcriptional start site located near a unique alternative (Alt) exon, homologous to E2-2Alt [71]. The presence of the Alt exon resulted in naming this E-protein HEBAlt, and referring to the canonical HEB as HEBCan.