Hox regulation of transcription: more complex(es)

Abstract

Hox genes encode transcription factors with important roles during embryogenesis and tissue differentiation. Genetic analyses initially demonstrated that interfering with Hox genes has profound effects on the specification of cell identity, suggesting that Hox proteins regulate very specific sets of target genes. However, subsequent biochemical analyses revealed that Hox proteins bind DNA with relatively low affinity and specificity. Furthermore, it became clear that a given Hox protein could activate or repress transcription, depending on the context. A resolution to these paradoxes presented itself with the discovery that Hox proteins do not function in isolation, but interact with other factors in complexes. The first such "cofactors" were members of the Extradenticle/Pbx and Homothorax/Meis/Prep families. However, the list of Hox-interacting proteins has continued to grow, suggesting that Hox complexes contain many more components than initially thought. Additionally, the activities of the various components and the exact mechanisms whereby they modulate the activity of the complex remain puzzling. Here, we review the various proteins known to participate in Hox complexes and discuss their likely functions. We also consider that Hox complexes of different compositions may have different activities and discuss mechanisms whereby Hox complexes may be switched between active and inactive states.

Keywords: CBP; HDAC; Meis; Pbx; Prep; cofactor; extradenticle; gene expression; homothorax.

Figure 1

A. Diagram of a generalized Hox transcription complex. The Hox protein (brown) is shown binding to DNA, as are cofactors (blue) that interact both with the Hox protein and adjacent DNA elements, while general factors (grey) are recruited solely via protein-protein interactions. B. Diagram of Hox, PBC and HMP family proteins. Hox, PBC and HMP proteins are shown schematically with N-termini to the left and C-termini to the right. The diagram is intended to represent one generic member of each family and is not drawn to scale. Interacting factors are listed above each protein family at the approximate location reported to contain the binding site for that factor. The dashed line in PBC indicates the longer C-terminus present in Pbx1A. Note that all members of a family may not engage in all interactions shown. For instance, Prep proteins may not interact with CBP or TORC. Also, interacting proteins for which binding sites have not been mapped are not shown – for instance, PBC proteins are reported to bind CBP, but the exact binding site in PBC has not been delineated.

Figure 2

Diagram of potential steps regulating Hox complex assembly. The formation of Hox complexes may be regulated at several steps. Step 1 represents translocation to the nucleus. Note that individual HMP and PBC proteins are cytoplasmic – as result of tethering in the cytoplasm, phosphorylation status, nuclear export and/or lack of a functional nuclear import signal – and enter the nucleus as HMP:PBC dimers, while Hox proteins appear to enter the nucleus on their own. In addition, interaction between HMP and PBC proteins promotes the stability of these proteins. Step 2 indicates modifications of complex components affecting complex assembly – in this case exemplified by phosphorylation of Hox proteins. Step 3 refers to the assembly of complexes on DNA, where the specific arrangement of binding sites may affect the type of complexes that can form. See text for further details.

Figure 3

Diagram of repressive and activating Hox transcription complexes. Hox transcription complexes may be converted from a repressive form (left side) to an activating form (right side) by signaling via the retinoic acid (RA), protein kinase A (PKA) or glycogen synthase kinase-3 (GSK-3) pathways. See text for details.