Antagonism Versus Cooperativity with TALE Cofactors at the Base of the Functional Diversification of Hox Protein Function

Abstract

Extradenticle (Exd) and Homothorax (Hth) function as positive transcriptional cofactors of Hox proteins, helping them to bind specifically their direct targets. The posterior Hox protein Abdominal-B (Abd-B) does not require Exd/Hth to bind DNA; and, during embryogenesis, Abd-B represses hth and exd transcription. Here we show that this repression is necessary for Abd-B function, as maintained Exd/Hth expression results in transformations similar to those observed in loss-of-function Abd-B mutants. We characterize the cis regulatory module directly regulated by Abd-B in the empty spiracles gene and show that the Exd/Hth complex interferes with Abd-B binding to this enhancer. Our results suggest that this novel Exd/Hth function does not require the complex to bind DNA and may be mediated by direct Exd/Hth binding to the Abd-B homeodomain. Thus, in some instances, the main positive cofactor complex for anterior Hox proteins can act as a negative factor for the posterior Hox protein Abd-B. This antagonistic interaction uncovers an alternative way in which MEIS and PBC cofactors can modulate Abd-B like posterior Hox genes during development.

Functional dissection of the splice variants of the Drosophila gene homothorax (hth)

“…A similar observation is made in the posterior part of the embryo. In the last abdominal segments Exd is cytoplasmic, even though Hth is present there (Rivas et al, 2013). This observation again suggests that the sole presence of Hth is not sufficient to translocate Exd into the nucleus.…”

To Be Specific or Not: The Critical Relationship Between Hox And TALE Proteins

“…In these examples, the binding sites mediating this type of regulation do not need to be specific for a single Hox paralog. This regulation often, but not always, depends on the TALE cofactors [14,16], illustrating the diversity of the underlying molecular mechanisms (see also below). Along the same lines, other target genes might be regulated by even more, or in principle all, Hox paralogs and are referred to as paralog non-specific 12,17] (Figure 2).…”

Cellular and molecular insights into Hox protein action

“…Using phenotypic and molecular analyses, it was shown that inappropriate maintenance of Exd/Hth expression in the posterior domain of the Drosophila embryo, where identity is specified by the posterior Hox gene AbdB, phenocopies AbdB loss of function (Rivas et al, 2013). Such an antagonistic relationship also applies to the repression of the limb-suppressing gene Distalless (Dll) by AbdB .…”