Evolutionarily conserved domains required for activation and repression functions of the Drosophila Hox protein Ultrabithorax

Tour, Ella; Hittinger, Chris Todd; McGinnis, William

doi:10.1242/dev.02138

Cited by 97 publications

(99 citation statements)

References 78 publications

(94 reference statements)

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“…It has been proposed that the large N-terminal part of Ubx and Scr is required for transcriptional activation in vivo (48). Our data show that this need not be the case for several Scr-specific functions.…”

Section: Discussionmentioning

confidence: 48%

“…S1) revealed the divergence of the N terminus of the protein in length and sequence, with the exception of the MSSYFVNS, the DYTQL and the SCKYA motifs. Both the fly (48) and the murine MSSYFVNS domain in flies (49) seem to be limited to contributing to transcriptional potency rather than specificity, because its deletion resulted in homeotic transformations (49) and ectopic activation of Scr target genes, albeit weaker than the wild type protein (48,49). Substitution of serine-10 by leucine in the Scr 14 hypomorphic allele only resulted in a mild decrease in the number of sex comb teeth in the adult (50).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Function and specificity of synthetic Hox transcription factors in vivo

Papadopoulos

Vukojević

Adachi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Homeotic (Hox) genes encode transcription factors that confer segmental identity along the anteroposterior axis of the embryo. However the molecular mechanisms underlying Hox-mediated transcription and the differential requirements for specificity in the regulation of the vast number of Hox-target genes remain ill-defined. Here we show that synthetic Sex combs reduced (Scr) genes that encode the Scr C terminus containing the homedomain (HD) and YPWM motif (Scr-HD) are functional in vivo. Synthetic Scr-HD peptides can induce ectopic salivary glands in the embryo and homeotic transformations in the adult fly, act as transcriptional activators and repressors during development, and participate in protein-protein interactions. Their transformation capacity was found to be enhanced over their full-length counterpart and mutations known to transform the full-length protein into constitutively active or inactive variants behaved accordingly in the synthetic peptides. Our results show that synthetic Scr-HD genes are sufficient for homeotic function in Drosophila and suggest that the N terminus of Scr has a role in transcriptional potency, rather than specificity. We also demonstrate that synthetic peptides behave largely in a predictable way, by exhibiting Scr-specific phenotypes throughout development, which makes them an important tool for synthetic biology.synthetic genes | transcriptional specificity | Hox genes | Sex combs reduced | homeotic transformations H omeotic genes code for transcription factors that play an instrumental role in animal development by specifying the identity of body segments along the anteroposterior axis of the embryo (1-4). Hox genes have persisted in the animal kingdom; they are found in animals as diverse as worms and humans (5, 6) and the Homeodomain (HD), a helix-turn-helix DNA-binding domain, has been strikingly conserved in animals since before the bilaterian split (1,7,8). Sequence-specific binding of Hox proteins has been studied for the Drosophila Sex combs reduced (Scr) (9, 10), Antennapedia (Antp) (11, 12) and Ultrabithorax (Ubx) (11, 12) HDs. A consensus sequence TAATC/GC/G recognition core was identified in all of them, which alone is obviously not sufficient to confer transcriptional specificity, because it occurs statistically every kilobase in the genome. Similar sequence preferences have been identified for Deformed (Dfd) and Abdominal-B (Abd-B) (11), raising the question of how target specificity is achieved among different Hox paralogs.A closer look into conserved residues outside the HD identified its amino-terminal YPWM motif that is present in almost all Hox proteins, from flies to vertebrates [with the exception of Abdominal-B (Abd-B), which has conserved only the tryptophan at position 3] (13). Extradenticle (Exd) and its mammalian homolog Pbx1 (14) were found to interact specifically with the YPWM motif of Hox proteins in vitro (15) and crystallographic analysis of a Ubx-Exd complex determined the topology of this interaction (16). Recently the link between the Ant...

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Function and specificity of synthetic Hox transcription factors in vivo

Papadopoulos

Vukojević

Adachi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Regardless of the inhibitory mechanism, YY1 binding to P1 attenuates but does not abolish transcription, and therefore, could finetune the amount of Hoxd4 transcript and protein levels available under specific conditions. A recent study in Drosophila suggests that the repressive effect of the HOX protein Ultrabithorax (UBX) on Distal-less (Dll) transcription in the limb is highly concentration-dependent (63). Therefore, YY1 might be required to fine-tune the appropriate amount of HOXD4 required to repress or activate downstream target genes.…”

Section: Discussionmentioning

confidence: 99%

Interplay between Chromatin and Trans-acting Factors Regulating the Hoxd4 Promoter during Neural Differentiation

Kobrossy

Rastegar

Featherstone

2006

Journal of Biological Chemistry

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Correct patterning of the antero-posterior axis of the embryonic trunk is dependent on spatiotemporally restricted Hox gene expression. In this study, we identified components of the Hoxd4 P1 promoter directing expression in neurally differentiating retinoic acid-treated P19 cells. We mapped three nucleosomes that are subsequently remodeled into an open chromatin state upon retinoic acid-induced Hoxd4 transcription. These nucleosomes spanned the Hoxd4 transcriptional start site in addition to a GC-rich positive regulatory element located 3 to the initiation site. We further identified two major cis-acting regulatory elements. An autoregulatory element was shown to recruit HOXD4 and its cofactor PBX1 and to positively regulate Hoxd4 expression in differentiating P19 cells. Conversely, the Polycomb group (PcG) protein Ying-Yang 1 (YY1) binds to an internucleosomal linker and represses Hoxd4 transcription before and during transcriptional activation. Sequential chromatin immunoprecipitation studies revealed that the PcG protein MEL18 was co-recruited with YY1 only in undifferentiated P19 cells, suggesting a role for MEL18 in silencing Hoxd4 transcription in undifferentiated P19 cells. This study links for the first time local chromatin remodeling events that take place during transcriptional activation with the dynamics of transcription factor association and DNA accessibility at a Hox regulatory region.Hox gene transcriptional activation marks the onset of an intricate series of events leading to proper embryonic patterning in all animals. The products of Hox genes, homeodomain-containing HOX transcription factors, are essential in specifying antero-posterior positional identity, hindbrain development, limb formation, and numerous additional morphogenetic and organogenetic events (1, 2). Given their crucial role in embryonic development, the genes encoding HOX proteins are highly conserved throughout the animal kingdom, and their expression is tightly regulated (3). In mammals, 39 Hox genes are organized into four clusters, each located on a different chromosome (1). Comparison of the clusters reveals 13 possible gene positions, although none of the clusters retains a full complement of 13 genes. Hox genes occupying the same positions are termed paralogs, sharing high sequence identity and functional redundancy. One can assign a 3Ј and a 5Ј end to a cluster since all genes are transcribed in the same direction. A unique feature of Hox gene clusters is a process termed "colinearity," correlating both the timing of transcriptional activation and the anterior expression borders with the position of a particular Hox gene along a cluster (4). Therefore, genes located more 3Ј are expressed earlier and have a more anterior expression border than genes located more 5Ј along the cluster. This observation and several other studies have led to the hypothesis that a sequential opening of chromatin, starting at the 3Ј end of a cluster and moving successively 5Ј, leads to the release of silencing, first at the 3Ј end, and seque...

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“…This issue could be addressed through the use of variants or chimeric Hox proteins. 19,68,69 Are there specific cofactors responsible for this differential specificity? (3) All the functions of Ubx and abdA in cardiogenesis occur in the absence of the only identified Hox cofactor, Exd.…”

Section: Future Directionsmentioning

confidence: 99%