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Mechanisms of Specificity for Hox Factor Activity Journal of Developmental Biology Review Mechanisms of Specificity for Hox Factor Activity Arya Zandvakili 1,2 and Brian Gebelein 3,* 1 Molecular and Developmental Biology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA 2 Medical-Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; [email protected] 3 Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA * Correspondence: [email protected]; Tel.: +1-513-636-3366 Academic Editors: Vincenzo Zappavigna and Simon J. Conway Received: 5 April 2016; Accepted: 4 May 2016; Published: 9 May 2016 Abstract: Metazoans encode clusters of paralogous Hox genes that are critical for proper development of the body plan. However, there are a number of unresolved issues regarding how paralogous Hox factors achieve specificity to control distinct cell fates. First, how do Hox paralogs, which have very similar DNA binding preferences in vitro, drive different transcriptional programs in vivo? Second, the number of potential Hox binding sites within the genome is vast compared to the number of sites bound. Hence, what determines where in the genome Hox factors bind? Third, what determines whether a Hox factor will activate or repress a specific target gene? Here, we review the current evidence that is beginning to shed light onto these questions. In particular, we highlight how cooperative interactions with other transcription factors (especially PBC and HMP proteins) and the sequences of cis-regulatory modules provide a basis for the mechanisms of Hox specificity. We conclude by integrating a number of the concepts described throughout the review in a case study of a highly interrogated Drosophila cis-regulatory module named “The Distal-less Conserved Regulatory Element” (DCRE). Keywords: Hox; transcription factor; cis-regulatory modules; DNA binding specificity 1. Introduction Hox proteins are a family of homeodomain-containing Transcription Factors (TFs) that are critical for regulating developmental processes in metazoans [1,2]. The stark homeotic changes occurring in Hox mutant animals, such as the classic antenna-to-leg transformations in Drosophila, testify to the importance of Hox factors for proper development [3]. In addition, more recent studies have demonstrated that Hox factors not only drive stereotypic developmental programs, but also have a role in maintaining differentiated cell populations [4,5]. Given that Hox factors are conserved from C. elegans to H. sapiens, a fundamental understanding of how Hox factors function will yield significant insights into both the development and evolution of body plans. The majority of metazoan genomes encode clusters of paralogous Hox genes (Figure1A). While invertebrates generally have one Hox cluster, vertebrates have multiple Hox clusters owing to duplications of the entire cluster during evolution [6]. The order of Hox genes within the clusters typically correlates with their expression pattern along the Anterior-Posterior (A-P) axis of the embryo [7–9]. Genes at the 31 end of a cluster are expressed in anterior regions of an embryo, whereas genes toward the 51 end are expressed in progressively more posterior regions of the embryo. Thus, the differential expression of Hox genes is a key step in the specification of distinct cell fates along the A-P axis. J. Dev. Biol. 2016, 4, 16; doi:10.3390/jdb4020016 www.mdpi.com/journal/jdb J. Dev. Biol. 2016, 4, 16 2 of 22 J. Dev. Biol. 2016, 4, 16 2 of 22 FigureFigure 1.1. SchematicSchematic ofof HoxHox genegene locuslocus andand HoxHox proteins.proteins. ((AA)) SchematicSchematic ofof HoxHox genegene clustersclusters inin C.C. eleganselegans,, D.D. melanogastermelanogaster andand M.M. musculus. Genes Genes with with similar similar colors colors ar aree thought thought to to derive derive from from a acommon common ancestor ancestor [10]; [10 ];(B) ( BSchematic) Schematic of a of Hox a Hox protein protein with with regions regions labeled labeled and described and described in boxes in boxes(bottom) (bottom) [11–18].[11 –18Per-amino-acid]. Per-amino-acid conservation conservation score score across across DrosophilaDrosophila HoxHox protein sequencessequences demonstratesdemonstrates that that the the HX HX and homeodomainand homeodomain regions re aregions the mostare the conserved most conserved regions across regions paralogous across Hoxparalogous proteins. Hox Multiple proteins. sequence Multiple alignment sequence was producedalignment viawas Clustal producedW (top) via [19 Clustal,20]. Note:Ω (top) The [19,20]. size of eachNote: Hox The protein size of regioneach Hox is not protein to scale. region is not to scale. AtAt thethe sequencesequence level,level, HoxHox proteinsproteins share share two two stereotypic stereotypic domains: domains: aa conservedconserved homeodomainhomeodomain andand a conserveda conserved Hexapeptide Hexapeptide (HX) (HX) motif motif that is that located is N-terminallocated N-terminal to the homeodomain to the homeodomain (Figure1B). Hox(Figure factors 1B). utilize Hox factors their homeodomains utilize their homeodomains to directly bind to DNA, directly and bind they DNA, share veryand similarthey share binding very preferencessimilar bindingin vitro preferencesas monomers in vitro [21 as–23 monomers]. The HX [21–23]. motif mediates The HX mot directif mediates interactions direct with interactions another familywith another of TFs family (PBC proteins), of TFs (PBC and proteins), it is separated and it fromis separated the homeodomain from the homeodomain by a flexible by and a flexible highly variableand highly linker variable region [linker12,13]. region Outside [12,13]. of the homeodomainOutside of the and homeodomain the HX motif, and Hox the protein HX motif, sequences Hox divergeprotein substantially;sequences diverge and while substantially; we largely and do while not understand we largely their do functions,not understand these non-conservedtheir functions, regionsthese non-conserved contain residues regions that cancontain be post-translationally residues that can be modified post-translationally and/or have modified been implicated and/or have in protein-proteinbeen implicated interactions in protein-protein and the interactions regulation of and transcriptional the regulation outputs of transcriptional [24–27]. outputs [24–27]. HoxHox factorsfactors specifyspecify cell-fatescell-fates basedbased onon theirtheir abilityability toto interactinteract withwithCis Cis-Regulatory-Regulatory ModulesModules (CRMs)(CRMs) and and to regulateto regulate transcription transcription [28,29 ].[28,29]. CRMs provideCRMs provide a DNA platforma DNA toplatform organize interactionsto organize betweeninteractions Hox between factors and Hox other factors proteins. and other Although proteins. Hox Although interactions Hox with interactions DNA and with other DNA proteins and haveother been proteins studied have extensively, been studied we extensively, still lack a comprehensivewe still lack a comprehens understandingive understanding of how specificity of how is achievedspecificity to is accurately achieved recognize to accurately and regulaterecognize target and genesregulate required target togenes direct required specific cellto direct fates. specific In this review,cell fates. we exploreIn this threereview, questions we explore related three to Hox ques specificity:tions related First, to how Hox do specificity: paralogous First, Hox proteinshow do driveparalogous different Hox cell fatesproteins even thoughdrive theydifferent utilize cell conserved fates homeodomainseven though withthey highlyutilize similar conserved DNA homeodomains with highly similar DNA binding preferences? Second, metazoan genomes contain a large number of potential Hox binding sites, yet only a subset of these sites are bound at any one J. Dev. Biol. 2016, 4, 16 3 of 22 binding preferences? Second, metazoan genomes contain a large number of potential Hox binding sites, yet only a subset of these sites are bound at any one time. What factors determine which sequences are bound and regulated by Hox proteins, whereas other sequences containing Hox binding sites remain unbound? Third, once bound, how does an individual Hox factor activate some target genes and repress others? Below, we present emerging evidence that provides new insight into the mechanisms that contribute to the specificity of Hox action. 2. Differentiation of Hox Paralog Activities A fundamental problem in the study of TF specificity is that most TFs are members of large protein families that have highly similar DNA binding properties yet distinct in vivo functions [30]. The Hox family of TFs is an exemplar of this problem. While paralogous Hox factors bind highly similar DNA sequences, genetic loss- and gain-of-function studies demonstrate that Hox factors control diverse cell fates along the A-P axis of metazoans [1,31]. Furthermore, in C. elegans, it has been demonstrated that paralogous Hox proteins have highly divergent genomic binding patterns in vivo [32]. However, it is not immediately clear whether this difference in in vivo function is due to differences in Hox paralogs or due to the fact that Hox paralogs are functioning in different cellular contexts. Several studies have controlled for cellular context and have demonstrated that paralogous Hox proteins have different in vivo activities within the same cell types. First, over- or under-expressing specific Hox paralogs within
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