Transcriptional regulation of the alternative sex hormone-binding globulin promoter by KLF4.

In most mammals the major site of sex hormone-binding globulin (SHBG) synthesis is the liver wherefrom it is secreted into the bloodstream and is the primary determinant of sex steroid access to target tissues. The minor site of SHBG synthesis is the testis and in lower mammals testicular SHBG has long been known to be synthesized and secreted by Sertoli cells. However, human testicular SHBG is expressed in developing germ cells from an upstream alternative promoter (altP-SHBG). Transcripts arising from this region comprise an alternative first exon (1A) with the resultant protein confined to the acrosomal compartment of the mature spermatozoa. I have dissected the regulatory components of the alternative SHBG promoter and identified motifs that are required for optimal transcriptional activity from this region. Transcriptional activity is driven by two CACCC elements that appear to be functionally redundant. The transcription factor KLF4 interacts with promoter the region spanning these elements in vivo. Knockdown of Klf4 results in decreased altP-SHBG activity, while Klf4 overexpression relieves the effects of knockdown. Based on their shared patterns of expression in vivo, I conclude that KLF4 is a transcriptional regulator of SHBG in male germ cells.