Coregulators: from whence came these "master genes".

It is now over a decade since the first nuclear receptor coactivator, SRC-1, was cloned and discovered to be a new type of transcription factor that does not bind DNA, but rather, binds directly or indirectly to nuclear receptors (NRs) to mediate their transcriptional potency. The NR coactivators belong to a class of molecules now termed ‘coregulators’. Employing an ‘operational’ definition, we define coactivators as molecules which enhance transcription, and corepressors as molecules which repress transcription. Current evidence indicates that this operational definition can be modified by gene, cell and signaling context for any one coregulator. Our current understanding is that NRs and other DNA-binding transcription factors (TFs) search out the target genes to be regulated by binding to specific DNA sequences (or other TFs at such sequences) termed TF-response elements (1); the second job of NRs is to recruit the coregulators that perform all of the subsequent reactions needed to induce or repress expression of genes. Initially, we believed that coactivators were simply ‘adapters’ that stabilized the general transcription machinery at the TATA box. This explanation proved to be incorrect. Over the past decade, the mechanistic importance of coregulators has expanded logarithmically, and we now realize that they perform virtually ‘all’ of the reactions needed for control of enhancer dependent gene expression.