Hox functional diversity: Novel insights from flexible motif folding and plastic protein interaction

Ortiz-Lombardı́a, M.; Foos, Nicolas; Maurel-Zaffran, Corinne; Saurin, Andrew J.; Graba, Yacine

doi:10.1002/bies.201600246

Cited by 7 publications

(5 citation statements)

References 64 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During development, HOX proteins can bind similar AT-rich DNA sequences in vitro (for reviews, see McGinnis and Krumlauf 1992;Gehring et al 1994;Lemons and McGinnis 2006). HOX proteins can heterodimerize with PBX/ Exd proteins (see Saadaoui et al 2011;Ladam and Sagerström 2014;Merabet and Mann 2016;Ortiz-Lombardia et al 2017) and can also pair with other classes of TFs for function; for example T-box factors, as recently described in limb development (Jain et al 2018). Through the years, heterodimerization with PBX/Exd has been proposed as a mechanism through which HOX proteins acquire DNA-binding selectivity and specificity.…”

Section: Partnerships Of Pbc Tfsmentioning

confidence: 99%

‘Building a perfect body’: control of vertebrate organogenesis by PBX-dependent regulatory networks

2019

View full text Add to dashboard Cite

Pbx genes encode transcription factors that belong to the TALE (three-amino-acid loop extension) superclass of homeodomain proteins. We have witnessed a surge in information about the roles of this gene family as leading actors in the transcriptional control of development. PBX proteins represent a clear example of how transcription factors can regulate developmental processes by combinatorial properties, acting within multimeric complexes to implement activation or repression of transcription depending on their interaction partners. Here, we revisit long-emphasized functions of PBX transcription factors as cofactors for HOX proteins, major architects of the body plan. We further discuss new knowledge on roles of PBX proteins in different developmental contexts as upstream regulators of Hox genes-as factors that interact with non-HOX proteins and can work independently of HOX-as well as potential pioneer factors. Committed to building a perfect body, PBX proteins govern regulatory networks that direct essential morphogenetic processes and organogenesis in vertebrate development. Perturbations of PBX-dependent networks can cause human congenital disease and cancer.

show abstract

Section: Partnerships Of Pbc Tfsmentioning

confidence: 99%

‘Building a perfect body’: control of vertebrate organogenesis by PBX-dependent regulatory networks

2019

View full text Add to dashboard Cite

show abstract

“…The homeobox genes encode a large superclass of TFs ( Garcia-Fernandez 2005 ; Hoegg and Meyer 2005 ; Pascual-Anaya et al 2012 ; Holland 2015 ; Ferrier 2016 ). They are characterized by encoding a homeodomain, which is usually 60 amino acids in length and folds to form a structure with three α-helices and an N-terminal domain ( Ortiz-Lombardia et al 2017 ). The third α-helix and N-terminal domain confer the specificity to the binding of the homeodomain to the major and minor groove of the DNA double helix, respectively ( Hanes and Brent 1991 ; Chu et al 2012 ; Ortiz-Lombardia et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…They are characterized by encoding a homeodomain, which is usually 60 amino acids in length and folds to form a structure with three α-helices and an N-terminal domain ( Ortiz-Lombardia et al 2017 ). The third α-helix and N-terminal domain confer the specificity to the binding of the homeodomain to the major and minor groove of the DNA double helix, respectively ( Hanes and Brent 1991 ; Chu et al 2012 ; Ortiz-Lombardia et al 2017 ). This conservation of sequence facilitates the characterization of many homeobox genes based solely on their homeodomain sequence ( Holland et al 2007 ), although there are also a variety of other DNA binding domains found in metazoan homeobox genes, which provide additional identification characteristics and biological functions ( Burglin and Affolter 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Homeobox Gene Duplication and Divergence in Arachnids

Leite

Baudouin-Gonzalez

Iwasaki-Yokozawa

et al. 2018

Molecular Biology and Evolution

187

View full text Add to dashboard Cite

Homeobox genes are key toolkit genes that regulate the development of metazoans and changes in their regulation and copy number have contributed to the evolution of phenotypic diversity. We recently identified a whole genome duplication (WGD) event that occurred in an ancestor of spiders and scorpions (Arachnopulmonata), and that many homeobox genes, including two Hox clusters, appear to have been retained in arachnopulmonates. To better understand the consequences of this ancient WGD and the evolution of arachnid homeobox genes, we have characterized and compared the homeobox repertoires in a range of arachnids. We found that many families and clusters of these genes are duplicated in all studied arachnopulmonates (Parasteatoda tepidariorum, Pholcus phalangioides, Centruroides sculpturatus, and Mesobuthus martensii) compared with nonarachnopulmonate arachnids (Phalangium opilio, Neobisium carcinoides, Hesperochernes sp., and Ixodes scapularis). To assess divergence in the roles of homeobox ohnologs, we analyzed the expression of P. tepidariorum homeobox genes during embryogenesis and found pervasive changes in the level and timing of their expression. Furthermore, we compared the spatial expression of a subset of P. tepidariorum ohnologs with their single copy orthologs in P. opilio embryos. We found evidence for likely subfunctionlization and neofunctionalization of these genes in the spider. Overall our results show a high level of retention of homeobox genes in spiders and scorpions post-WGD, which is likely to have made a major contribution to their developmental evolution and diversification through pervasive subfunctionlization and neofunctionalization, and paralleling the outcomes of WGD in vertebrates.

show abstract

“…Examples include: posterior Hox factors have greater affinity for adjacent Hth/Meis sites than anterior Hox factors [44,45], and Hox interactions with Exd/Pbx proteins via the Hox hexapeptide motif (YPWM) can uncover latent DNA binding specificity that better discriminates between Hox factors [19]. More recently, subsets of Hox factors have been shown to mediate additional interactions with Pbx/Exd proteins via specific PBC-interaction motifs (SPIMs) [14,15]. While SPIM interactions between Hox and PBC proteins are thought to be weaker and more dynamic than those mediated by the classic YPWM motif, it is possible they further aid in the ability of Hox factors to bind distinct DNA sequences.…”

Section: Discussionmentioning

confidence: 99%

“…A partial explanation for this phenomenon is that Hox factors form transcription factor complexes with additional proteins. The Extradenticle (Exd, Drosophila)/Pbx (vertebrate) and Homothorax (Hth, Drosophila)/Meis (vertebrate) families of transcription factors represent the best characterized Hox co-factor proteins [11][12][13][14][15]. Exd/Pbx and Hth/Meis proteins are widely expressed during development and bind DNA in a cooperative manner with Hox factors as well as with each other.…”

Section: Introductionmentioning

confidence: 99%

Thecis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements inDrosophila

Zandvakili

Uhl

Campbell

et al. 2018

Preprint

View full text Add to dashboard Cite

Hox genes encode a family of transcription factors that, despite having similar in vitro DNA binding preferences, regulate distinct genetic programs along the metazoan anterior-posterior axis. To better define mechanisms of Hox specificity, we compared and contrasted the ability of abdominal Hox factors to regulate two cis-regulatory elements within the Drosophila embryo. Both the Ultrabithorax (Ubx) and Abdominal-A (Abd-A) Hox factors form cooperative complexes with the Extradenticle (Exd) and Homothorax (Hth) transcription factors to repress the distal-less leg selector gene via the DCRE, whereas only Abd-A interacts with Exd and Hth on the RhoA element to activate a rhomboid serine protease gene that stimulates Epidermal Growth Factor secretion.By swapping binding sites between these elements, we found that the RhoA Exd/Hth/Hox site configuration that mediates Abd-A specific activation can also convey transcriptional repression by both Ubx and Abd-A when placed into the DCRE, but only in one orientation. We further show that the orientation and spacing of Hox sites relative to additional transcription factor binding sites within the RhoA and DCRE elements is critical to mediate appropriate cell-and segment-specific output. These results indicate that the interaction between Hox, Exd, and Hth neither determines activation vs repression specificity nor defines Ubx vs Abd-A specificity. Instead the precise integration of Hox sites with additional TF inputs is required for accurate transcriptional output.Taken together, these studies provide new insight into the mechanisms of Hox target and regulatory specificity as well as the constraints placed on regulatory elements to convey appropriate outputs. Author SummaryThe Hox genes encode a family of transcription factors that give cells within each region along the developing body plan a unique identity in animals from worms to mammals. Surprisingly, however, most of the Hox factors bind the same or highly similar DNA sequences. These findings raise a paradox: How can proteins that have highly similar DNA binding properties perform different functions in the animal by regulating different sets of target genes? In this study, we address this question by studying how two Hox factors regulate the expression of target genes that specify leg development and the making of liver-like cells in the developing fly. By comparing and contrasting how Hox target genes are activated and/or repressed, we found that the same Hox binding sites can mediate either activation or repression in a manner that depends upon context. In addition, we found that a Hox binding site that is normally regulated by only one Hox factor, can also be used by more than one Hox factor swapped into another target gene. These findings indicate that the specificity of a Hox factor to regulate target genes does not rely solely upon DNA binding specificity but also requires regulatory specificity.

show abstract

Hox functional diversity: Novel insights from flexible motif folding and plastic protein interaction

Cited by 7 publications

References 64 publications

‘Building a perfect body’: control of vertebrate organogenesis by PBX-dependent regulatory networks

‘Building a perfect body’: control of vertebrate organogenesis by PBX-dependent regulatory networks

Homeobox Gene Duplication and Divergence in Arachnids

Thecis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements inDrosophila

Contact Info

Product

Resources

About