scholarly journals Hox genes in the coordination of embryonic development. Model of hourglass in the description of vertebrate ontogenesis

2021 ◽  
Vol 11 (12) ◽  
pp. 24-37
Author(s):  
Sergey Dolomatov ◽  
Vera Kazakova ◽  
Walery Zukow
Keyword(s):  
Embryonic Development ◽  
Tissue Regeneration ◽  
Target Genes ◽  
Hox Genes ◽  
Development Model ◽  
Tissue Morphogenesis ◽  
Hox Proteins ◽  
Temporal And Spatial

The paper analyzes the role of HOX genes in the processes of embryonic development of vertebrates. Based on the analysis, it is concluded that HOX genes are the most important regulators of embryonic development. The HOX genes predominantly realize their influence through specific HOX proteins that have the ability to regulate the expression of target genes. The order of expression of the HOX genes, as a rule, obeys the rule of temporal and spatial colinearity. This mechanism determines the temporal and spatial course of tissue morphogenesis during embryonic development and tissue regeneration in organisms that have reached the stage of maturity. The process of embryo morphogenesis, determined by highly conserved HOX genes, explains the appearance of the phylotypic period - the stage of embryonic development of vertebrates, at which embryos of different classes of vertebrates have distinct morphological similarities.

Homeotic response elements are tightly linked to tissue-specific elements in a transcriptional enhancer of the teashirt gene

Development ◽  
1995 ◽  
Vol 121 (9) ◽  
pp. 2799-2812 ◽  
Author(s):  
A. McCormick ◽  
N. Core ◽  
S. Kerridge ◽  
M.P. Scott
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Hox Genes ◽  
Zinc Finger Protein ◽  
Cell Types ◽  
Transcriptional Enhancer ◽  
Hox Proteins ◽  
Tissue Specific ◽  
Conserved Sequences

Along the anterior-posterior axis of animal embryos, the choice of cell fates, and the organization of morphogenesis, is regulated by transcription factors encoded by clustered homeotic or ‘Hox’ genes. Hox genes function in both epidermis and internal tissues by regulating the transcription of target genes in a position- and tissue-specific manner. Hox proteins can have distinct targets in different tissues; the mechanisms underlying tissue and homeotic protein specificity are unknown. Light may be shed by studying the organization of target gene enhancers. In flies, one of the target genes is teashirt (tsh), which encodes a zinc finger protein. tsh itself is a homeotic gene that controls trunk versus head development. We identified a tsh gene enhancer that is differentially activated by Hox proteins in epidermis and mesoderm. Sites where Antennapedia (Antp) and Ultrabithorax (Ubx) proteins bind in vitro were mapped within evolutionarily conserved sequences. Although Antp and Ubx bind to identical sites in vitro, Antp activates the tsh enhancer only in epidermis while Ubx activates the tsh enhancer in both epidermis and in somatic mesoderm. We show that the DNA elements driving tissue-specific transcriptional activation by Antp and Ubx are separable. Next to the homeotic protein-binding sites are extensive conserved sequences likely to control tissue activation by different homeodomain proteins. We propose that local interactions between homeotic proteins and other factors effect activation of targets in proper cell types.

Role of the HOXA cluster in HSC emergence and blood cancer

2021 ◽  
Author(s):  
Mays Abuhantash ◽  
Emma M. Collins ◽  
Alexander Thompson
Keyword(s):  
Embryonic Development ◽  
Hox Genes ◽  
Hoxa Cluster ◽  
Hematopoietic Stem ◽  
Blood Cancer ◽  
Non Coding Rna ◽  
Blood Formation ◽  
Peripheral Cells ◽  
Normal Embryonic Development

Hematopoiesis, the process of blood formation, is controlled by a complex developmental program that involves intrinsic and extrinsic regulators. Blood formation is critical to normal embryonic development and during embryogenesis distinct waves of hematopoiesis have been defined that represent the emergence of hematopoietic stem or progenitor cells. The Class I family of homeobox (HOX) genes are also critical for normal embryonic development, whereby mutations are associated with malformations and deformity. Recently, members of the HOXA cluster (comprising 11 genes and non-coding RNA elements) have been associated with the emergence and maintenance of long-term repopulating HSCs. Previous studies identified a gradient of HOXA expression from high in HSCs to low in circulating peripheral cells, indicating their importance in maintaining blood cell numbers and differentiation state. Indeed, dysregulation of HOXA genes either directly or by genetic lesions of upstream regulators correlates with a malignant phenotype. This review discusses the role of the HOXA cluster in both HSC emergence and blood cancer formation highlighting the need for further research to identify specific roles of these master regulators in normal and malignant hematopoiesis.

scholarly journals Both Pbx1 and E2A-Pbx1 bind the DNA motif ATCAATCAA cooperatively with the products of multiple murine Hox genes, some of which are themselves oncogenes.

1995 ◽  
Vol 15 (7) ◽  
pp. 3786-3795 ◽  
Author(s):  
Q Lu ◽  
P S Knoepfler ◽  
J Scheele ◽  
D D Wright ◽  
M P Kamps
Keyword(s):  
Dna Binding ◽  
Target Genes ◽  
Hox Genes ◽  
Physical Interaction ◽  
Homeodomain Protein ◽  
Structural Development ◽  
Cell Leukemia ◽  
Homeodomain Proteins ◽  
Hox Proteins

E2A-PBX1 is the oncogene produced at the t(1;19) chromosomal breakpoint of pediatric pre-B-cell leukemia. Expression of E2A-Pbx1 induces fibroblast transformation and myeloid and T-cell leukemia in mice and arrests differentiation of granulocyte macrophage colony-stimulating factor-dependent myeloblasts in cultured marrow. Recently, the Drosophila melanogaster protein Exd, which is highly related to Pbx1, was shown to bind DNA cooperatively with the Drosophila homeodomain proteins Ubx and Abd-A. Here, we demonstrate that the normal Pbx1 homeodomain protein, as well as its oncogenic derivative, E2A-Pbx1, binds the DNA sequence ATCAATCAA cooperatively with the murine Hox-A5, Hox-B7, Hox-B8, and Hox-C8 homeodomain proteins, which are themselves known oncoproteins, as well as with the Hox-D4 homeodomain protein. Cooperative binding to ATCAATCAA required the homeodomain-dependent DNA-binding activities of both Pbx1 and the Hox partner. In cotransfection assays, Hox-B8 suppressed transactivation by E2A-Pbx1. These results suggest that (i) Pbx1 may participate in the normal regulation of Hox target gene transcription in vivo and therein contribute to aspects of anterior-posterior patterning and structural development in vertebrates, (ii) that E2A-Pbx1 could abrogate normal differentiation by altering the transcriptional regulation of Hox target genes in conjunction with Hox proteins, and (iii) that the oncogenic mechanism of certain Hox proteins may require their physical interaction with Pbx1 as a cooperating, DNA-binding partner.

Hox repression of a target gene: extradenticle-independent, additive action through multiple monomer binding sites

Development ◽  
2002 ◽  
Vol 129 (13) ◽  
pp. 3115-3126 ◽  
Author(s):  
Ron Galant ◽  
Christopher M. Walsh ◽  
Sean B. Carroll
Keyword(s):  
Binding Sites ◽  
Target Gene ◽  
Target Genes ◽  
Hox Genes ◽  
Regulatory Element ◽  
Morphological Diversity ◽  
Hox Proteins ◽  
Cis Element ◽  
Additive Action ◽  
Hox Protein

Homeotic (Hox) genes regulate the identity of structures along the anterior-posterior axis of most animals. The low DNA-binding specificities of Hox proteins have raised the question of how these transcription factors selectively regulate target gene expression. The discovery that the Extradenticle (Exd)/Pbx and Homothorax (Hth)/Meis proteins act as cofactors for several Hox proteins has advanced the view that interactions with cofactors are critical to the target selectivity of Hox proteins. It is not clear, however, to what extent Hox proteins also regulate target genes in the absence of cofactors. In Drosophila melanogaster, the Hox protein Ultrabithorax (Ubx) promotes haltere development and suppresses wing development by selectively repressing many genes of the wing-patterning hierarchy, and this activity requires neither Exd nor Hth function. Here, we show that Ubx directly regulates a flight appendage-specific cis-regulatory element of the spalt (sal) gene. We find that multiple monomer Ubx-binding sites are required to completely repress this cis-element in the haltere, and that individual Ubx-binding sites are sufficient to mediate its partial repression. These results suggest that Hox proteins can directly regulate target genes in the absence of the cofactor Extradenticle. We propose that the regulation of some Hox target genes evolves via the accumulation of multiple Hox monomer binding sites. Furthermore, because the development and morphological diversity of the distal parts of most arthropod and vertebrate appendages involve Hox, but not Exd/Pbx or Hth/Meis proteins, this mode of target gene regulation appears to be important for distal appendage development and the evolution of appendage diversity.

The Mir-17-92 Cluster Contributes to MLL Leukemia through the Repression of PKNOX1, a MEIS1 Competitor

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 877-877
Author(s):  
Yousaf A Mian ◽  
Nancy J. Zeleznik-Le
Keyword(s):  
Target Genes ◽  
Hox Genes ◽  
Regulatory Mechanism ◽  
Conflicts Of Interest ◽  
Chromosome Translocation ◽  
Transcriptional Elongation ◽  
Terminal Portion ◽  
Partner Protein ◽  
Carboxy Terminal

Abstract Leukemias which arise as a result of translocations between the MLL gene and one of more than 80 different partner genes have a relatively poor prognosis. As a result of chromosome translocation, the carboxy-terminal portion of MLL containing the H3K4 methyltransferase domain is replaced by partner protein domains. In most cases this causes constitutive recruitment of transcriptional elongation machinery to MLL target genes. Downstream targets of MLL are aberrantly upregulated and include developmentally important HOX genes and MEIS1, as well as multiple microRNAs. Here we examine the contribution of specific miRNAs in the miR-17-92 cluster to MLL leukemia through the use of custom antagomiR oligonucleotides. Combinatorial treatment with antagomiRs against miR-17 and miR-19a dramatically reduce colony forming ability of MLL-fusion containing cells, but not non-MLL AML controls. To determine the mechanism by which these miRNAs contribute to leukemia, we validated PKNOX1 as a target of both miR-17 and miR-19a. MEIS1 and PKNOX1 are TALE domain proteins that participate in ternary complexes with HOX and PBX proteins. Here we establish the competitive relationship between PKNOX1 and MEIS1 in PBX-containing complex formation and determine the antagonistic role of Pknox1 to leukemia in a murine MLL-AF9 model. Collectively, these data implicate the miR-17-92 cluster as part of a regulatory mechanism necessary to maintain MEIS1/HOXA9 -mediated transformation in MLL leukemia. This approach represents a paradigm where targeting multiple non-homologous miRNAs may be utilized as a novel therapeutic regimen. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dynamic MicroRNA Expression Profiles During Embryonic Development Provide Novel Insights Into Cardiac Sinus Venosus/Inflow Tract Differentiation

2022 ◽  
Vol 9 ◽  
Author(s):  
Carlos Garcia-Padilla ◽  
Angel Dueñas ◽  
Diego Franco ◽  
Virginio Garcia-Lopez ◽  
Amelia Aranega ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Target Genes ◽  
Hox Genes ◽  
Cardiac Development ◽  
Expression Profiles ◽  
Primitive Streak ◽  
Sinus Venosus ◽  
Luciferase Assay ◽  
Microrna Target ◽  
Cardiac Looping

MicroRNAs have been explored in different organisms and are involved as molecular switches modulating cellular specification and differentiation during the embryonic development, including the cardiovascular system. In this study, we analyze the expression profiles of different microRNAs during early cardiac development. By using whole mount in situ hybridization in developing chick embryos, with microRNA-specific LNA probes, we carried out a detailed study of miR-23b, miR-130a, miR-106a, and miR-100 expression during early stages of embryogenesis (HH3 to HH17). We also correlated those findings with putative microRNA target genes by means of mirWalk and TargetScan analyses. Our results demonstrate a dynamic expression pattern in cardiac precursor cells from the primitive streak to the cardiac looping stages for miR-23b, miR-130a, and miR-106a. Additionally, miR-100 is later detectable during cardiac looping stages (HH15-17). Interestingly, the sinus venosus/inflow tract was shown to be the most representative cardiac area for the convergent expression of the four microRNAs. Through in silico analysis we revealed that distinct Hox family members are predicted to be targeted by the above microRNAs. We also identified expression of several Hox genes in the sinus venosus at stages HH11 and HH15. In addition, by means of gain-of-function experiments both in cardiomyoblasts and sinus venosus explants, we demonstrated the modulation of the different Hox clusters, Hoxa, Hoxb, Hoxc, and Hoxd genes, by these microRNAs. Furthermore, we correlated the negative modulation of several Hox genes, such as Hoxa3, Hoxa4, Hoxa5, Hoxc6, or Hoxd4. Finally, we demonstrated through a dual luciferase assay that Hoxa1 is targeted by miR-130a and Hoxa4 is targeted by both miR-23b and miR-106a, supporting a possible role of these microRNAs in Hox gene modulation during differentiation and compartmentalization of the posterior structures of the developing venous pole of the heart.

scholarly journals A Systematic Review on HOX Genes as Potential Biomarkers in Colorectal Cancer: An Emerging Role of HOXB9

2021 ◽  
Vol 22 (24) ◽  
pp. 13429
Author(s):  
Eirini Martinou ◽  
Giulia Falgari ◽  
Izhar Bagwan ◽  
Angeliki M. Angelidi
Keyword(s):  
Poor Prognosis ◽  
Tumour Growth ◽  
Hox Genes ◽  
Distant Metastases ◽  
Metastatic Potential ◽  
Hox Proteins ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
The Impact

Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64–10.43, I2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC.

Hox proteins have different affinities for a consensus DNA site that correlate with the positions of their genes on the hox cluster

1994 ◽  
Vol 14 (7) ◽  
pp. 4532-4545
Author(s):  
I Pellerin ◽  
C Schnabel ◽  
K M Catron ◽  
C Abate
Keyword(s):  
Dna Binding ◽  
Target Genes ◽  
Hox Genes ◽  
Regulatory Elements ◽  
Binding Properties ◽  
Hox Proteins ◽  
Hox Cluster ◽  
Dna Binding Properties

The hox genes, members of a family of essential developmental regulators, have the intriguing property that their expression in the developing murine embryo is colinear with their chromosomal organization. Members of the hox gene family share a conserved DNA binding domain, termed the homeodomain, which mediates interactions of Hox proteins with DNA regulatory elements in the transcriptional control regions of target genes. In this study, we characterized the DNA binding properties of five representative members of the Hox family: HoxA5, HoxB4, HoxA7, HoxC8, and HoxB1. To facilitate a comparative analysis of their DNA binding properties, we produced the homeodomain regions of these Hox proteins in Escherichia coli and obtained highly purified polypeptides. We showed that these Hox proteins interact in vitro with a common consensus DNA site that contains the motif (C/G)TAATTG. We further showed that the Hox proteins recognize the consensus DNA site in vivo, as determined by their ability to activate transcription through this site in transient transfection assays. Although they interact optimally with the consensus DNA site, the Hox proteins exhibit subtle, but distinct, preferences for DNA sites that contain variations of the nucleotides within the consensus motif. In addition to their modest differences in DNA binding specificities, the Hox proteins also vary in their relative affinities for DNA. Intriguingly, their relative affinities correlate with the positions of their respective genes on the hox cluster. These findings suggest that subtle differences in DNA binding specificity combined with differences in DNA binding affinity constitute features of the "Hox code" that contribute to the selective functions of Hox proteins during murine embryogenesis.

Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut

Development ◽  
1995 ◽  
Vol 121 (10) ◽  
pp. 3163-3174 ◽  
Author(s):  
D.J. Roberts ◽  
R.L. Johnson ◽  
A.C. Burke ◽  
C.E. Nelson ◽  
B.A. Morgan ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Target Genes ◽  
Hox Genes ◽  
Ectopic Expression ◽  
Secreted Protein ◽  
Gut Development ◽  
Visceral Mesoderm ◽  
Homologous Genes ◽  
Inductive Signal

Reciprocal inductive signals between the endoderm and mesoderm are critical to vertebrate gut development. Sonic hedgehog encodes a secreted protein known to act as an inductive signal in several regions of the developing embryo. In this report, we provide evidence to support the role of Sonic hedgehog and its target genes Bmp-4 and the Abd-B-related Hox genes in the induction and patterning the chick hindgut. Sonic is expressed in the definitive endoderm at the earliest stage of chick gut formation. Immediately subjacent to Sonic expression in the caudal endoderm is undifferentiated mesoderm, later to become the visceral mesoderm of the hindgut. Genes expressed within this tissue include Bmp-4 (a TGF-beta relative implicated in proper growth of visceral mesoderm) and members of the Abd-B class of Hox genes (known regulators of pattern in many aspects of development). Using virally mediated misexpression, we show that Sonic hedgehog is sufficient to induce ectopic expression of Bmp-4 and specific Hoxd genes within the mesoderm. Sonic therefore appears to act as a signal in an epithelial-mesenchymal interaction in the earliest stages of chick hindgut formation. Gut pattern is evidenced later in gut morphogenesis with the presence of anatomic boundaries reflecting phenotypically and physiologically distinct regions. The expression pattern of the Abd-b-like Hox genes remains restricted in the hindgut and these Hox expression domains reflect gut morphologic boundaries. This finding strongly supports a role for these genes in determining the adult gut phenotype. Our results provide the basis for a model to describe molecular controls of early vertebrate hindgut development and patterning. Expression of homologous genes in Drosophila suggest that aspects of gut morphogenesis may be regulated by similar inductive networks in the two organisms.

Role of Hox genes in regulating digit patterning

2018 ◽  
Vol 62 (11-12) ◽  
pp. 797-805 ◽  
Author(s):  
Rocío Pérez-Gómez ◽  
Endika Haro ◽  
Marc Fernández-Guerrero ◽  
María F. Bastida ◽  
María A. Ros
Keyword(s):  
Sonic Hedgehog ◽  
Selection Pressure ◽  
Distal Part ◽  
Hox Genes ◽  
Extensive Study ◽  
Functional Adaptation ◽  
Digit Number ◽  
Hox Proteins ◽  
Self Organizing

The distal part of the tetrapod limb, the autopod, is characterized by the presence of digits. The digits display a wide diversity of shapes and number reflecting selection pressure for functional adaptation. Despite extensive study, the different aspects of digit patterning, as well as the factors and mechanisms involved are not completely understood. Here, we review the evidence implicating Hox proteins in digit patterning and the interaction between Hox genes and the Sonic hedgehog/Gli3 pathway, the other major regulator of digit number and identity. Currently, it is well accepted that a self-organizing Turing-type mechanism underlies digit patterning, this being understood as the establishment of an iterative arrangement of digit/interdigit in the hand plate. We also discuss the involvement of 5’ Hox genes in regulating digit spacing in the digital plate and therefore the number of digits formed in this self-organizing system.

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