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Philosophical Transactions of the Royal... Feb 2017Gene duplications and gene losses have been frequent events in the evolution of animal genomes, with the balance between these two dynamic processes contributing to... (Review)
Review
Gene duplications and gene losses have been frequent events in the evolution of animal genomes, with the balance between these two dynamic processes contributing to major differences in gene number between species. After gene duplication, it is common for both daughter genes to accumulate sequence change at approximately equal rates. In some cases, however, the accumulation of sequence change is highly uneven with one copy radically diverging from its paralogue. Such 'asymmetric evolution' seems commoner after tandem gene duplication than after whole-genome duplication, and can generate substantially novel genes. We describe examples of asymmetric evolution in duplicated homeobox genes of moths, molluscs and mammals, in each case generating new homeobox genes that were recruited to novel developmental roles. The prevalence of asymmetric divergence of gene duplicates has been underappreciated, in part, because the origin of highly divergent genes can be difficult to resolve using standard phylogenetic methods.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'.
Topics: Animals; Biological Evolution; Evolution, Molecular; Genes, Duplicate; Genes, Homeobox; Growth and Development
PubMed: 27994121
DOI: 10.1098/rstb.2015.0480 -
Development (Cambridge, England) Jan 2023Hox genes encode evolutionarily conserved transcription factors that are essential for the proper development of bilaterian organisms. Hox genes are unique because they...
Hox genes encode evolutionarily conserved transcription factors that are essential for the proper development of bilaterian organisms. Hox genes are unique because they are spatially and temporally regulated during development in a manner that is dictated by their tightly linked genomic organization. Although their genetic function during embryonic development has been interrogated, less is known about how these transcription factors regulate downstream genes to direct morphogenetic events. Moreover, the continued expression and function of Hox genes at postnatal and adult stages highlights crucial roles for these genes throughout the life of an organism. Here, we provide an overview of Hox genes, highlighting their evolutionary history, their unique genomic organization and how this impacts the regulation of their expression, what is known about their protein structure, and their deployment in development and beyond.
Topics: Humans; Embryonic Development; Gene Expression Regulation, Developmental; Genes, Homeobox; Homeodomain Proteins; Morphogenesis; Transcription Factors; Animals
PubMed: 36645372
DOI: 10.1242/dev.192476 -
The International Journal of... 2018This year marks the 40th anniversary of the discovery by Ed Lewis of the property of collinearity in the bithorax gene complex in Drosophila. This landmark work... (Review)
Review
This year marks the 40th anniversary of the discovery by Ed Lewis of the property of collinearity in the bithorax gene complex in Drosophila. This landmark work illustrated the need to understand regulatory mechanisms that coordinate expression of homeotic gene clusters. Through the efforts of many groups, investigation of the Hox gene family has generated many fundamental findings on the roles and regulation of this conserved gene family in development, disease and evolution. This has led to a number of important conceptual advances in gene regulation and evolutionary biology. This article presents some of the history and advances made through studies on Hox gene clusters.
Topics: Animals; Body Patterning; Gene Expression Regulation, Developmental; Genes, Homeobox; Genetics; History, 20th Century; History, 21st Century
PubMed: 30604835
DOI: 10.1387/ijdb.180330rr -
The International Journal of... 2018Forty years ago, Ed Lewis established for the first time the organization of homeotic genes along the chromosome and its importance in embryo patterning. To celebrate...
Forty years ago, Ed Lewis established for the first time the organization of homeotic genes along the chromosome and its importance in embryo patterning. To celebrate this seminal discovery, the International Journal of Developmental Biology decided to launch a Special Issue. It is with honor, pleasure, but also humility that we accepted the challenge of acting as guest editors for this Special Issue. We entitled the issue Hox genes: past, present and future of master regulator genes since despite four decades of amazing discoveries, numerous questions remain unanswered, which open new avenues of research. This is well-acknowledged by Robb Krumlauf and Jacqueline Deschamps in the Introductory articles. The high-level reviews and original research reports collected in this Special Issue also reflect the wide-range and important topics that are still in the spotlights including the origins of Hox genes, the regulatory events controlling their expression, the mechanisms driving the action of HOX proteins, and their multiple roles in normal development and pathogenesis.
Topics: Animals; Body Patterning; Developmental Biology; Gene Expression Regulation, Developmental; Genes, Homeobox
PubMed: 30604834
DOI: 10.1387/ijdb.180332fg -
Molecular Biology and Evolution Sep 2018Homeobox 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... (Comparative Study)
Comparative Study
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.
Topics: Animals; Arachnida; Embryonic Development; Evolution, Molecular; Gene Duplication; Gene Expression; Genes, Homeobox; Multigene Family; Transcriptome
PubMed: 29924328
DOI: 10.1093/molbev/msy125 -
Chromosoma Jun 2016Here, we provide an update of our review on homeobox genes that we wrote together with Walter Gehring in 1994. Since then, comprehensive surveys of homeobox genes have... (Review)
Review
Here, we provide an update of our review on homeobox genes that we wrote together with Walter Gehring in 1994. Since then, comprehensive surveys of homeobox genes have become possible due to genome sequencing projects. Using the 103 Drosophila homeobox genes as example, we present an updated classification. In animals, there are 16 major classes, ANTP, PRD, PRD-LIKE, POU, HNF, CUT (with four subclasses: ONECUT, CUX, SATB, and CMP), LIM, ZF, CERS, PROS, SIX/SO, plus the TALE superclass with the classes IRO, MKX, TGIF, PBC, and MEIS. In plants, there are 11 major classes, i.e., HD-ZIP (with four subclasses: I to IV), WOX, NDX, PHD, PLINC, LD, DDT, SAWADEE, PINTOX, and the two TALE classes KNOX and BEL. Most of these classes encode additional domains apart from the homeodomain. Numerous insights have been obtained in the last two decades into how homeodomain proteins bind to DNA and increase their specificity by interacting with other proteins to regulate cell- and tissue-specific gene expression. Not only protein-DNA base pair contacts are important for proper target selection; recent experiments also reveal that the shape of the DNA plays a role in specificity. Using selected examples, we highlight different mechanisms of homeodomain protein-DNA interaction. The PRD class of homeobox genes was of special interest to Walter Gehring in the last two decades. The PRD class comprises six families in Bilateria, and tinkers with four different motifs, i.e., the PAIRED domain, the Groucho-interacting motif EH1 (aka Octapeptide or TN), the homeodomain, and the OAR motif. Homologs of the co-repressor protein Groucho are also present in plants (TOPLESS), where they have been shown to interact with small amphipathic motives (EAR), and in yeast (TUP1), where we find an EH1-like motif in MATα2.
Topics: Amino Acid Sequence; Animals; Base Sequence; Drosophila melanogaster; Gene Expression Regulation; Genes, Homeobox; Homeodomain Proteins; Transcription Factors
PubMed: 26464018
DOI: 10.1007/s00412-015-0543-8 -
International Journal of Molecular... Nov 2023homeobox genes have been extensively studied for their role in development, especially in neuroectoderm formation. Recently, their expression has also been reported in... (Review)
Review
homeobox genes have been extensively studied for their role in development, especially in neuroectoderm formation. Recently, their expression has also been reported in adult physiological and pathological tissues, including retina, mammary and pituitary glands, sinonasal mucosa, in several types of cancer, and in response to inflammatory, ischemic, and hypoxic stimuli. Reactivation of genes in adult tissues supports the notion of the evolutionary amplification of functions of genes by varying their temporal expression, with the selection of homeobox genes from the "toolbox" to drive or contribute to different processes at different stages of life. OTX involvement in pathologies points toward these genes as potential diagnostic and/or prognostic markers as well as possible therapeutic targets.
Topics: Otx Transcription Factors; Genes, Homeobox; Retina; Homeodomain Proteins; Gene Expression Regulation, Developmental
PubMed: 38069286
DOI: 10.3390/ijms242316962 -
International Journal of Molecular... Oct 2022Homeobox genes encode transcription factors regulating basic developmental processes. They are arranged according to sequence similarities of their conserved homeobox in...
Homeobox genes encode transcription factors regulating basic developmental processes. They are arranged according to sequence similarities of their conserved homeobox in 11 classes, including TALE. Recently, we have reported the so-called TALE-code. This gene signature describes physiological expression patterns of all active TALE-class homeobox genes in the course of hematopoiesis. The TALE-code allows the evaluation of deregulated TALE homeobox genes in leukemia/lymphoma. Here, we extended the TALE-code to include the stages of pro-B-cells and pre-B-cells in early B-cell development. Detailed analysis of the complete lineage of B-cell differentiation revealed expression of TALE homeobox genes IRX1 and MEIS1 exclusively in pro-B-cells. Furthermore, we identified aberrant expression of IRX2, IRX3 and MEIS1 in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) which originates from early B-cell progenitors. The data showed correlated activities of deregulated TALE-class members with particular BCP-ALL subtype markers, namely IRX2 with TCF3/E2A-fusions, IRX3 with ETV6/TEL-fusions, and MEIS1 with KMT2A/MLL-fusions. These correlations were also detected in BCP-ALL cell lines which served as experimental models. We performed siRNA-mediated knockdown experiments and reporter gene assays to analyze regulatory connections. The results showed mutual activation of IRX1 and TCF3. In contrast, IRX2 directly repressed wild-type TCF3 while the fusion gene TCF3::PBX1 lost the binding site for IRX2 and remained unaltered. IRX3 mutually activated fusion gene ETV6::RUNX1 while activating itself by aberrantly expressed transcription factor KLF15. Finally, KMT2A activated MEIS1 which in turn supported the expression of IRX3. In summary, we revealed normal TALE homeobox gene expression in early B-cell development and identified aberrant activities of IRX2, IRX3 and MEIS1 in particular subtypes of BCP-ALL. Thus, these TALE homeobox genes may serve as novel diagnostic markers and therapeutic targets.
Topics: Core Binding Factor Alpha 2 Subunit; Genes, Homeobox; Homeodomain Proteins; Humans; Myeloid Ecotropic Viral Integration Site 1 Protein; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; RNA, Small Interfering
PubMed: 36233173
DOI: 10.3390/ijms231911874 -
International Journal of Molecular... Feb 2022The double homeobox ) gene, encoding a double homeobox transcription factor, is one of the key drivers of totipotency in mice. Recent studies showed Dux was temporally... (Review)
Review
The double homeobox ) gene, encoding a double homeobox transcription factor, is one of the key drivers of totipotency in mice. Recent studies showed Dux was temporally expressed at the 2-cell stage and acted as a transcriptional activator during zygotic genome activation (ZGA) in embryos. A similar activation occurs in mouse embryonic stem cells, giving rise to 2-cell-like cells (2CLCs). Though the molecular mechanism underlying this expanded 2CLC potency caused by Dux activation has been partially revealed, the regulation mechanisms controlling Dux expression remain elusive. Here, we discuss the latest advancements in the multiple levels of regulation of Dux expression, as well as Dux function in 2CLCs transition, aiming to provide a theoretical framework for understanding the mechanisms that regulate totipotency.
Topics: Animals; Embryonic Development; Gene Expression Regulation, Developmental; Genes, Homeobox; Genome; Homeodomain Proteins; Humans; Transcription Factors; Zygote
PubMed: 35216182
DOI: 10.3390/ijms23042067 -
PloS One 2018Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation. Several members of the NKL subclass are deregulated...
Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation. Several members of the NKL subclass are deregulated in T-cell progenitors and support leukemogenesis. We have recently described particular expression patterns of nine NKL homeobox genes in early hematopoiesis and T-cell development. Here, we screened NKL homeobox gene activities in normal B-cell development and extended the NKL-code to include this lymphoid lineage. Analysis of public expression profiling datasets revealed that HHEX and NKX6-3 were the only members differentially active in naïve B-cells, germinal center B-cells, plasma cells and memory B-cells. Subsequent examination of different types of B-cell malignancies showed both aberrant overexpression of NKL-code members and ectopic activation of subclass members physiologically silent in lymphopoiesis including BARX2, DLX1, EMX2, NKX2-1, NKX2-2 and NKX3-2. Based on these findings we performed detailed studies of the B-cell specific NKL homeobox gene NKX6-3 which showed enhanced activity in patient subsets of follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL), and in three DLBCL cell lines to serve as in vitro models. While excluding genomic and chromosomal rearrangements at the locus of NKX6-3 (8p11) promoter studies demonstrated that B-cell factors MYB and PAX5 activated NKX6-3 transcription. Furthermore, aberrant BMP7/SMAD1-signalling and deregulated expression of chromatin complex components AUTS2 and PCGF5 promoted NKX6-3 activation. Finally, NKL homeobox genes HHEX, HLX, MSX1 and NKX6-3 were expressed in B-cell progenitors and generated a regulatory gene network in cell lines which we propose may provide physiological support for NKL-code formation in early B-cell development. Together, we identified an NKL-code in B-cell development whose violation may deregulate differentiation and promote malignant transformation.
Topics: B-Lymphocytes; Cell Differentiation; Cell Line; Gene Expression; Gene Expression Profiling; Genes, Homeobox; Homeobox Protein Nkx-2.2; Homeodomain Proteins; Humans; Lymphoma; Nuclear Proteins; Transcription Factors
PubMed: 30308041
DOI: 10.1371/journal.pone.0205537