Yamamoto was ahead of his time...

During the year I was born, Michael's old mentor published a review on steroid receptor regulation of gene networks (looking at all interesting angles of how these TF regulate gene expression).

Of course this piece below caught my eye....and it seems even more relevant today now that we have the technology to address genome wide studies. It may be less interesting since its steriod receptors but permissiveness and synergism may still apply to RXR. HERE's the complete paper.


Multifactor Regulation

Determinants of cell-specific gene networks can be viewed as static controls that are superimposed stably upon steroid RE function. In addition, there are dynamic controls that can have profound modulatory effects. Thus, hormone­ regulated genes are commonly controlled by multiple hormones and factors, and the characteristics of multifactor regulation are often more complex than those predicted by simple additivity of the effects of the individual regulators . Synergistic and permissive effects of two or more hormones upon the expres­ sion of single gene have been widely documented. For example, McKnight and coworkers (51; G. S. McKnight, personal communication) showed that es­ tradiol induction of ovalbumin transcription in oviduct tissue occurs only in the presence of insulin, while neither hormone alone is active. In some cases, permissive effects reflect the induction by one hormone of functional receptors for the second; thus, estradiol appears to permit progesterone and androgen induction of ovalbumin synthesis at least in part by inducing the appearance of progesterone and androgen receptors in oviduct cells (191). The permissive effect of insulin upon estrogen induction of ovalbumin differs, however, since transferrin induction by estradiol in the absence of insulin (51) shows that competent estrogen receptors are constitutively present.

A complementary pair of permissive effects has been described in rat HTC cells. In that system, cAMP alone fails to stimulate the expression of the tyrosine aminotransferase gene, but dexamethasone permits cAMP to act as a strong inducer (78); conversely, glucocorticoids have no effect on plasminogen activator mRNA production in HTC cells, whereas prior or simultaneous treatment with cAMP permits strong dexamethasone induction of plasminogen activator gene expression (68).

Little is known about the nature of permissive and synergistic effects of any two (or more) hormones. Posttranscriptional and/or posttranslational phe­ nomena (e.g. see 56) are likely to contribute in some cases to overall patterns of multifactor regulation, but these effects can also occur solely at the level of transcription. Such multifactor responses may reflect the differential activities of two or more distinct enhancers upon a single promoter under particular physiological conditions . To approach this notion experimentally, DeFranco et al (39; see also 225) constructed a simple recombinant plasmid into which two different enhancers could be inserted at positions where each could potentially act upon a specific promoter, itself inserted at a third position where it would lead to the production of an easily assayed "reporter" gene product; constructs bearing different enhancer and promoter combinations could then be trans­ fected into a variety of cell types. Using such plasmids containing an MTV GRE and a second heterologous enhancer, DeFranco et al discovered that the patterns of expression observed depended upon all three variables--enhancers , promoter, and cell type . Transfections in the presence or absence of glucocorti­ coids revealed that in certain combinations the paired enhancers stimulated promoter activity synergistically; in some cases activation of the GRE enhancer was required (i.e. "permissive") for function of an otherwise cryptic second enhancer.