Chapter 3 Hox Specificity: Unique Roles for Cofactors and Collaborators
Section snippets
An Introduction to the Problem
Hox proteins are homeodomain‐containing transcription factors that have the capacity to carry out exquisitely precise functions in vivo that are critical for many aspects of animal morphogenesis. Most typically, each Hox gene is expressed in a subset of the anterior‐posterior (AP) body axis, where it specifies cellular and tissue identities. Famous examples of the power that Hox genes have to sculpt animal morphogenesis include the antenna‐to‐leg transformation caused by the Antennapedia (Antp)
Too Many Binding Sites, Not Enough Specificity
Because all Hox proteins have a homeodomain, understanding how Hox proteins recognize their DNA‐binding sites in vivo certainly depends, at least in part, on how this 60 amino acid domain recognizes DNA sequences. The basic DNA recognition principles for homeodomains were established from biochemical and structural studies (reviewed previously by Gehring et al., 1994). These studies show that all homeodomains fold into a bundle of three alpha‐helices and an unstructured “N‐terminal” arm. DNA
How Specific Do Hox Proteins Need to be?
Hox biologists can readily point to highly specific functions that are uniquely specified by individual Hox proteins. For example, in Drosophila, only the Hox gene Sex combs reduced (Scr) can orchestrate the development of a salivary gland, presumably by regulating a network of salivary gland‐promoting genes (Bradley et al., 2001). The flip view that multiple Hox proteins probably share many targets is typically given less attention. We believe this discussion is highly relevant to how one
Hox Cofactors
Given that some Hox functions truly require a high degree of specificity, and that Hox homeodomains, themselves, are not sufficiently discriminating to account for this specificity, how is specificity achieved? One well‐established way in which Hox proteins achieve specificity in vivo is to bind DNA cooperatively with other DNA‐binding cofactors. To date, the best‐characterized cofactors are all TALE (three amino acid loop extension) homeodomain proteins (Mann and Chan, 1996, Moens and Selleri,
What Do In Vivo Hox‐Binding Sites Look Like?
An important approach to understand how Hox proteins regulate target gene expression, and to reveal potential generalizations, is to examine the cis‐regulatory elements they directly bind to in vivo. Once a set of in vivo‐validated Hox‐targeted cis‐regulatory elements are in hand, several questions can be asked. These include: How many also require input from known cofactors? How many Hox‐binding sites are present in each element?, and What other regulatory inputs are there? To provide initial
Insights into Hox Specificity from Structural Studies
Several monomeric homeodomain‐DNA structures have been solved, and all reveal a very similar mode of DNA recognition by this DNA‐binding domain (Gehring et al., 1994). Briefly, the third alpha‐helix, also called the recognition helix, lies in the major groove of the DNA, where it makes several direct and water‐mediated contacts with specific bases and the phosphate backbone. Ile47, Gln50, Asn51, and Met54, residues that are present in all Hox homeodomains, are primarily responsible for making
Activity Regulation of Hox Proteins: The Role of Hox Collaborators
Although TALE family proteins clearly play an important role in DNA‐binding site recognition, Hox proteins use these cofactors to both activate and repress target genes, raising the question of how gene activation versus repression is determined. Although there is currently only one example, one answer is that Hox proteins may use dedicated repressors, such as En, as Hox cofactors in gene repression (Gebelein et al., 2004). Another possibility, which will be no surprise to people used to
Insights into Hoxasome Function from cis‐Regulatory Element Architecture
One straightforward view for how Hoxasomes function is that, once assembled, they recruit coactivators, corepressors, and/or chromatin remodeling complexes that ultimately carry out transcriptional regulation much like any other enhanceosome. Indeed, consistent with this view, there have been numerous reports describing direct interactions between Hox proteins and/or TALE cofactors with these more general components of the transcriptional machinery (Chariot et al., 1999, Prince et al., 2008,
Conclusions
In this review, we have summarized a wide range of mechanisms that Hox proteins employ to regulate their target genes. For one, Hox proteins often require cofactors to bind to their binding sites in paralog‐specific and semi‐paralog‐specific target genes. Cofactors may not be as essential, however, for shared Hox functions or those executed by Hox proteins in a unique regulatory environment, such as the Drosophila haltere. Structural studies have suggested that TALE family cofactors not only
Acknowledgments
We thank Matthew Slattery for comments on the manuscript and Barry Honig for discussions related to this review. This work was supported by an NIH RO1 grant awarded to R.S.M.
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2024, Seminars in Cell and Developmental BiologyCitation Excerpt :These proteins are highly conserved during evolution, with the presence of one (such as Extradenticle (Exd) or Homothorax (Hth) in Drosophila) or more (such as PBX1–4 or MEIS1–2 in human) representatives. PBC and MEIS cofactors interact on DNA with all Hox members and modulate both their DNA-binding properties and trans-regulatory activities [5,6]. In most cases, PBC/MEIS form trimeric complexes with the Hox protein, and the assembly of Hox/PBC/MEIS complexes has been described to rely on diverse Hox protein motifs in several instances [6].