The human CREM gene spans 14 exons and is highly conserved throughout evolution (Figure 1A); the human and mouse CREM genes are approximately 90% homologous at the level of the coding nucleotides [26]. The multitude of CREM isoforms (>20 in humans) is achieved with differential splicing processes and the use of alternative promoters, transcription factor repertoires, and initiation codons (Figure 1B). Several stimuli, including adrenergic signals or an increase in the levels of intracellular cAMP or glucose induce the expression of the ICER isoform, which was initially thought to be the only inducible CREM isoform [27]. Transcription of ICER depends on an intronic promoter within the 3′-region of the CREM gene (Figure 1A) [28]. Transcription of the longer CREM variants, including CREMα, is orchestrated by two promoters at the 5′-end of the gene, one directly upstream of exon I (denoted P1) and a second upstream of exon II (denoted P2). It has been documented that CREMα expression is increased in T cells from SLE patients at the transcriptional and protein levels [22–24], mediated by the promoter P1 whose activity level mirrors disease severity.
