Over the last quarter century, more than 532 genes have been put forward as regulatory targets of retinoic acid. In some cases this control is direct, driven by a liganded heterodimer of retinoid receptors bound to a DNA response element; in others, it is indirect, reflecting the actions of intermediate transcription factors, non-classical associations of receptors with other proteins, or even more distant mechanisms. Given the broad range of scientific questions continually under investigation, researchers do not always have occasion to classify target genes along these lines. However, our understanding of the genetic role of retinoids will be enhanced if such a distinction can be made for each regulated gene. We have therefore evaluated published data from 1,191 papers covering 532 genes and have classified these genes into four categories according to the degree to which an hypothesis of direct versus indirect control is supported overall. We found 27 genes that are unquestionably direct targets of the classical pathway in permissive cellular contexts (Category 3 genes), plus 105 genes that appear to be candidates, pending the results of specific additional experiments (Category 2). Data on another 267 targets are not evocative of direct or indirect regulation either way, although control by retinoic acid through some mechanism is clear (Category 1). Most of the remaining 133 targets seem to be regulated indirectly, usually through a transcriptional intermediary, in the contexts studied so far (Category 0). -Balmer, J. E., and R. Blomhoff BackgroundBeginning in at least the late 1960s, there was tremendous interest in whether the differentiating and tumor suppressing activities of retinoids reflected a genetic mechanism, on analogy to the steroid hormones, or an epigenetic one. It had been known for some time that retinoids could influence mRNA levels in certain cells, but also that they could increase activity on membrane-bound ribosomes. Any number of different mechanisms were possible, and quite a few were proposed. In a particularly

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The remodeling of transcription factor binding sites is one of the major engines of evolutionary change, yet almost all available examples of this involve sites from regulatory modules brought online during development. Developmental modules are known to enjoy some type of canalization, which allows considerably more cryptic change than would be assumed for nondevelopmental modules. It remains an open question, then, how frequently binding site remodeling occurs in general. There are strong intuitive reasons to expect that regulatory constancy, and hence binding site conservation in general, is the rule, yet little systematic work has been done to verify this. In the present article, we show that the most obvious way of approaching this problem--which is simply to collect experimentally verified binding sites from the literature without further analysis, create multispecies alignments, and apply conservation algorithms--leads to counterintuitive and ultimately inaccurate results. This is because of the low complexity of typical binding sites and, consequently, because of the frequency with which strings resembling legitimate sites occur throughout the genome. In vitro results can easily be confounded by this. Applying one traditional conservation algorithm and two novel algorithms to a data set that ought to be representative of binding sites in general, but which is taken from the literature directly, we find that only 58% of sites appear to be conserved. However, after the data set is carefully vetted against binding site overloading, and after the likelihood of a specific type of compensatory evolution is evaluated, conservation rates as high as 94% appear reasonable.

Beginning in the late 1980s, Eric Davidson's group at Cal Tech developed a modularity hypothesis of developmental gene regulation, showing that in an expanding number of cases, particular aspects of development were governed by compact ‘modules’ of transcription factor binding sites (TFBSs), and that these modules were separable, complex and interconnected. Davidson made no attempt to further generalize the hypothesis, but others took up the idea, transported it out of development and extended it to a general rule of clustering. Despite such misbegotten origins, the ‘extended’ modularity hypothesis—that TFBSs in general tend to come in compact clusters—has been highly productive, yet it has never been challenged with a large, diverse and unbiased dataset to see how universal it actually is. The aim of the present paper is to do so. Applying human–mouse–rat phylogenetic footprinting to neighbourhoods of a diverse set of TFBSs, including both developmental and non-developmental signals, we find that the extended hypothesis holds in at least 93.5% of cases. Based on this particular sample, we found a mean module length of 609 nucleotides containing, on an average, 24.5 presumptive regulatory signals of length greater than 5 and averaging 8.5 nucleotides each.