The anterior Hox gene ceh-13 and elt-1/GATA activate the posterior Hox genes nob-1 and php-3 to specify posterior lineages in the C. elegans embryo

AbstractHox transcription factors play a conserved role in specifying positional identity during animal development, with posterior Hox genes typically repressing the expression of more anterior Hox genes. Here, we dissect the regulation of the posterior Hox genes nob-1 and php-3 in the nematode C. elegans. We show that nob-1 and php-3 are co-expressed in gastrulation-stage embryos in cells that express the anterior Hox gene ceh-13. This expression is controlled by several partially redundant transcriptional enhancers. Surprisingly, these enhancers require ceh-13 for expression, providing an example of an anterior Hox gene positively regulating a posterior Hox gene. Several other regulators also act positively through nob-1/php-3 enhancers, including elt-1/GATA, ceh-20/ceh-40/Pbx, unc-62/Meis, pop-1/TCF, ceh-36/Otx and unc-30/Pitx. We identified defects in both cell position and cell division patterns in ceh-13 and nob-1;php-3 mutants, suggesting that these factors regulate lineage identity in addition to positional identity. Together, our results highlight the complexity and remarkable flexibility of Hox gene regulation and function.

Download Full-text

Functional dominance among Hox genes: repression dominates activation in the regulation of Dpp

Development ◽

10.1242/dev.125.24.4949 ◽

1998 ◽

Vol 125 (24) ◽

pp. 4949-4957 ◽

Cited By ~ 3

Author(s):

M. Capovilla ◽

J. Botas

Keyword(s):

Gene Regulation ◽

Target Gene ◽

Hox Genes ◽

Hox Gene ◽

Visceral Mesoderm ◽

Positional Identity ◽

The One

Here we investigate the mechanisms by which Hox genes compete for the control of positional identity. Functional dominance is often observed where different Hox genes are co-expressed, and frequently the more posteriorly expressed Hox gene is the one that prevails, a phenomenon known as posterior prevalence. We use dpp674, a visceral mesoderm-specific enhancer of decapentaplegic (dpp), to investigate functional dominance among Hox genes molecularly. We find that posterior prevalence does not adequately describe the regulation of dpp by Hox genes. Instead, we find that abdominal-A (abd-A) dominates over the more posterior Abdominal-B (Abd-B) and the more anterior Ultrabithorax (Ubx). In the context of the dpp674 enhancer, abd-A functions as a repressor whereas Ubx and Abd-B function as activators. Thus, these results suggest that other cases of Hox competition and functional dominance may also be understood in terms of competition for target gene regulation in which repression dominates over activation.

Download Full-text

A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans

Development ◽

10.1242/dev.126.1.37 ◽

1999 ◽

Vol 126 (1) ◽

pp. 37-49 ◽

Cited By ~ 9

Author(s):

J.N. Maloof ◽

J. Whangbo ◽

J.M. Harris ◽

G.D. Jongeward ◽

C. Kenyon

Keyword(s):

Gene Expression ◽

Wnt Signaling ◽

Wnt Pathway ◽

Hox Genes ◽

Wnt Signaling Pathway ◽

Beta Catenin ◽

Hox Gene ◽

C Elegans ◽

Neuroblast Migration ◽

Pathway Gene

The specification of body pattern along the anteroposterior (A/P) body axis is achieved largely by the actions of conserved clusters of Hox genes. Limiting expression of these genes to localized regional domains and controlling the precise patterns of expression within those domains is critically important for normal patterning. Here we report that egl-20, a C. elegans gene required to activate expression of the Hox gene mab-5 in the migratory neuroblast QL, encodes a member of the Wnt family of secreted glycoproteins. We have found that a second Wnt pathway gene, bar-1, which encodes a beta-catenin/Armadillo-like protein, is also required for activation of mab-5 expression in QL. In addition, we describe the gene pry-1, which is required to limit expression of the Hox genes lin-39, mab-5 and egl-5 to their correct local domains. We find that egl-20, pry-1 and bar-1 all function in a linear genetic pathway with conserved Wnt signaling components, suggesting that a conserved Wnt pathway activates expression of mab-5 in the migratory neuroblast QL. Moreover, we find that members of this Wnt signaling system play a major role in both the general and fine-scale control of Hox gene expression in other cell types along the A/P axis.

Download Full-text

A class act: conservation of homeodomain protein functions

Development ◽

10.1242/dev.1994.supplement.61 ◽

1994 ◽

Vol 1994 (Supplement) ◽

pp. 61-77 ◽

Cited By ~ 2

Author(s):

J. Robert Manak ◽

Matthew P. Scott

Keyword(s):

Gene Function ◽

Target Genes ◽

Hox Genes ◽

Homeobox Gene ◽

Homeodomain Protein ◽

Animal Development ◽

Protein Functions ◽

Unified View ◽

Protein Classes ◽

And Function

Dramatic successes in identifying vertebrate homeobox genes closely related to their insect relatives have led to the recognition of classes within the homeodomain superfamily. To what extent are the homeodomain protein classes dedicated to specific functions during development? Although information on vertebrate gene functions is limited, existing evidence from mice and nematodes clearly supports conservation of function for the Hox genes. Less compelling, but still remarkable, is the conservation of other homeobox gene classes and of regulators of homeotic gene expression and function. It is too soon to say whether the cases of conservation are unique and exceptional, or the beginning of a profoundly unified view of gene regulation in animal development. In any case, new questions are raised by the data: how can the differences between mammals and insects be compatible with conservation of homeobox gene function? Did the evolution of animal form involve a proliferation of new homeodomain proteins, new modes of regulation of existing gene types, or new relationships with target genes, or is evolutionary change largely the province of other classes of genes? In this review, we summarize what is known about conservation of homeobox gene function.

Download Full-text

ARID1B is a Dosage-sensitive Regulator of Polycomb Repressive Complex Distribution and HOX Gene Regulation in Patient-derived Neural Progenitors

10.21203/rs.3.rs-959800/v1 ◽

2021 ◽

Author(s):

Gerald Crabtree ◽

Esther Son ◽

Andrey Krokhotin ◽

Sai Gourisankar ◽

Chiung-Ying Chang

Keyword(s):

Gene Regulation ◽

Hox Genes ◽

De Novo ◽

Histone H2a ◽

Hox Gene ◽

Neural Lineage ◽

Evolutionarily Conserved ◽

Sequencing Studies ◽

A Subunit ◽

Activity Dependent

Abstract Recent unbiased exome and whole-genome sequencing studies have identified ARID1B (originally BAF250b) as the most frequently mutated gene in human de novo neurodevelopmental disorders and a high confidence autism gene. ARID1B is a subunit of the multimeric SWI/SNF or Brg/Brahma-Associated Factor (BAF) ATP-dependent chromatin remodeling complex. Studies of Arid1b+/- mice as well as other BAF subunit mutants have found defects in neural progenitor proliferation and activity-dependent neuronal dendritogenesis; however, to date, the molecular impact of ARID1B mutations on the human neural lineage has not been investigated. Remarkably, ARID1B is required for expression of HOX genes, including anterior HOX genes necessary for brain development. Despite the high homology with ARID1A and the fact that ARID1A is expressed at about 3-fold higher levels, it is unable to compensate for heterozygous loss of ARID1B. These changes in gene expression were paralleled by dosage-sensitive altered deposition of histone H3 lysine-27 trimethylation (H3K27me3) and histone H2A lysine-119 ubiquitination (H2AK119ub) indicating that an evolutionarily conserved pathway of HOX gene regulation underlies the neurodevelopmental defects accompanying ARID1B haploinsufficiency. Using FIRE-Cas9, we show that the unmutated ARID1B allele can be activated to near normal and potentially therapeutic levels.

Download Full-text

Interplay of RFX transcription factors 1, 2 and 3 in motile ciliogenesis

Nucleic Acids Research ◽

10.1093/nar/gkaa625 ◽

2020 ◽

Vol 48 (16) ◽

pp. 9019-9036

Author(s):

Sylvain Lemeille ◽

Marie Paschaki ◽

Dominique Baas ◽

Laurette Morlé ◽

Jean-Luc Duteyrat ◽

...

Keyword(s):

Transcription Factors ◽

Transcriptional Control ◽

Ex Vivo ◽

Ependymal Cells ◽

Clear Understanding ◽

Animal Development ◽

C Elegans ◽

And Function ◽

Redundant Functions

Abstract Cilia assembly is under strict transcriptional control during animal development. In vertebrates, a hierarchy of transcription factors (TFs) are involved in controlling the specification, differentiation and function of multiciliated epithelia. RFX TFs play key functions in the control of ciliogenesis in animals. Whereas only one RFX factor regulates ciliogenesis in C. elegans, several distinct RFX factors have been implicated in this process in vertebrates. However, a clear understanding of the specific and redundant functions of different RFX factors in ciliated cells remains lacking. Using RNA-seq and ChIP-seq approaches we identified genes regulated directly and indirectly by RFX1, RFX2 and RFX3 in mouse ependymal cells. We show that these three TFs have both redundant and specific functions in ependymal cells. Whereas RFX1, RFX2 and RFX3 occupy many shared genomic loci, only RFX2 and RFX3 play a prominent and redundant function in the control of motile ciliogenesis in mice. Our results provide a valuable list of candidate ciliary genes. They also reveal stunning differences between compensatory processes operating in vivo and ex vivo.

Download Full-text

Methylation in HOX Clusters and Its Applications in Cancer Therapy

Cells ◽

10.3390/cells9071613 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1613 ◽

Cited By ~ 2

Author(s):

Ana Paço ◽

Simone Aparecida de Bessa Garcia ◽

Renata Freitas

Keyword(s):

Gene Expression ◽

Cancer Therapy ◽

Hox Genes ◽

Treatment Options ◽

Chemotherapy Resistance ◽

Migration And Invasion ◽

Aberrant Expression ◽

Hox Gene ◽

Positional Identity ◽

Near Future

HOX genes are commonly known for their role in embryonic development, defining the positional identity of most structures along the anterior–posterior axis. In postembryonic life, HOX gene aberrant expression can affect several processes involved in tumorigenesis such as proliferation, apoptosis, migration and invasion. Epigenetic modifications are implicated in gene expression deregulation, and it is accepted that methylation events affecting HOX gene expression play crucial roles in tumorigenesis. In fact, specific methylation profiles in the HOX gene sequence or in HOX-associated histones are recognized as potential biomarkers in several cancers, helping in the prediction of disease outcomes and adding information for decisions regarding the patient’s treatment. The methylation of some HOX genes can be associated with chemotherapy resistance, and its identification may suggest the use of other treatment options. The use of epigenetic drugs affecting generalized or specific DNA methylation profiles, an approach that now deserves much attention, seems likely to be a promising weapon in cancer therapy in the near future. In this review, we summarize these topics, focusing particularly on how the regulation of epigenetic processes may be used in cancer therapy.

Download Full-text

egl-27 generates anteroposterior patterns of cell fusion in C. elegans by regulating Hox gene expression and Hox protein function

Development ◽

10.1242/dev.126.15.3303 ◽

1999 ◽

Vol 126 (15) ◽

pp. 3303-3312 ◽

Cited By ~ 1

Author(s):

Q. Ch'ng ◽

C. Kenyon

Keyword(s):

Gene Expression ◽

Cell Fusion ◽

Protein Function ◽

Hox Genes ◽

Positional Information ◽

Cell Fates ◽

Hox Proteins ◽

Hox Gene ◽

C Elegans ◽

Hox Protein

Hox genes pattern the fates of the ventral ectodermal Pn.p cells that lie along the anteroposterior (A/P) body axis of C. elegans. In these cells, the Hox genes are expressed in sequential overlapping domains where they control the ability of each Pn.p cell to fuse with the surrounding syncytial epidermis. The activities of Hox proteins are sex-specific in this tissue, resulting in sex-specific patterns of cell fusion: in hermaphrodites, the mid-body cells remain unfused, whereas in males, alternating domains of syncytial and unfused cells develop. We have found that the gene egl-27, which encodes a C. elegans homologue of a chromatin regulatory factor, specifies these patterns by regulating both Hox gene expression and Hox protein function. In egl-27 mutants, the expression domains of Hox genes in these cells are shifted posteriorly, suggesting that egl-27 influences A/P positional information. In addition, egl-27 controls Hox protein function in the Pn.p cells in two ways: in hermaphrodites it inhibits MAB-5 activity, whereas in males it permits a combinatorial interaction between LIN-39 and MAB-5. Thus, by selectively modifying the activities of Hox proteins, egl-27 elaborates a simple Hox expression pattern into complex patterns of cell fates. Taken together, these results implicate egl-27 in the diversification of cell fates along the A/P axis and suggest that chromatin reorganization is necessary for controlling Hox gene expression and Hox protein function.

Download Full-text

Functional differences between HOX proteins conferred by two residues in the homeodomain N-terminal arm.

Molecular and Cellular Biology ◽

10.1128/mcb.14.8.5066 ◽

1994 ◽

Vol 14 (8) ◽

pp. 5066-5075 ◽

Cited By ~ 27

Author(s):

M L Phelan ◽

R Sadoul ◽

M S Featherstone

Keyword(s):

Dna Binding ◽

Transcriptional Activation ◽

Hox Genes ◽

Functional Difference ◽

Recognition Sequence ◽

Embryonic Axes ◽

Alpha Helices ◽

Core Motif ◽

Hox Gene ◽

Positional Identity

Hox genes encode homeodomain-containing transcriptional regulators that function during development to specify positional identity along embryonic axes. The homeodomain is composed of a flexible N-terminal arm and three alpha helices, and it differentially binds DNA. A number of homeodomains recognize sites containing a TAAT core motif. The product of the murine Hoxd-4 (Hox-4.2) gene functions in a positive autoregulatory fashion in P19 cells that is dependent on two TAAT motifs in the Hoxd-4 promoter. This effect is specific in that murine HOXA-1 (HOX-1.6) is unable to activate transcription through the Hoxd-4 autoregulatory element. Here we show that this is due to an inability of the HOXA-1 homeodomain to bind a HOXD-4 recognition site effectively. We have produced chimeras between HOXD-4 and HOXA-1 to map specific residues responsible for this functional difference. When positions 2 and 3 in the N-terminal arm of HOXA-1 were converted to HOXD-4 identity, both strong DNA binding and transcriptional activation were rescued. This substitution appears to confer an increased DNA-binding ability on the HOXA-1 homeodomain, since we were unable to detect a high-affinity recognition sequence for HOXA-1 in a randomized pool of DNA probes. The contribution of position 3 to DNA binding has been implicated by structural studies, but this is the first report of the importance of position 2 in regulating homeodomain-DNA interactions. Additionally, specific homeodomain residues that confer major differences in DNA binding and transcriptional activation between Hox gene products have not been previously determined. Identity at these two positions is generally conserved among paralogs but varies between Hox gene subfamilies. As a result, these residues may be important for the regulation of target gene expression by specific Hox products.

Download Full-text

Uniaxial loading induces a scalable switch in cortical actomyosin flow polarization and reveals mechanosensitive regulation of cytokinesis

10.1101/560433 ◽

2019 ◽

Author(s):

Deepika Singh ◽

Devang Odedra ◽

Christian Pohl

Keyword(s):

Cell Division ◽

Stress Response ◽

Mechanical Stress ◽

Rotational Flow ◽

Mechanical Forces ◽

Longitudinal Flow ◽

Contractile Ring ◽

Animal Development ◽

C Elegans ◽

Cortical Fibers

AbstractDuring animal development, it is crucial that cells can sense and adapt to mechanical forces from their environment. Ultimately, these forces are transduced through the actomyosin cortex. How the cortex can simultaneously respond to and create forces during cytokinesis is not well understood. Here we show that under mechanical stress, cortical actomyosin flow switches its polarization during cytokinesis in the C. elegans embryo. In unstressed embryos, longitudinal cortical flows contribute to contractile ring formation, while rotational cortical flow is additionally induced in uniaxially loaded embryos. Rotational cortical flow is required for the redistribution of the actomyosin cortex in loaded embryos. Rupture of longitudinally aligned cortical fibers during cortex rotation releases tension, initiates orthogonal longitudinal flow and thereby contributes to furrowing in loaded embryos. A targeted screen for factors required for rotational flow revealed that actomyosin regulators involved in RhoA regulation, cortical polarity and chirality are all required for rotational flow and become essential for cytokinesis under mechanical stress. In sum, our findings extend the current framework of mechanical stress response during cell division and show scaling of orthogonal cortical flows to the amount of mechanical stress.

Download Full-text

The expression of the C. elegans labial-like Hox gene ceh-13 during early embryogenesis relies on cell fate and on anteroposterior cell polarity

Development ◽

10.1242/dev.124.21.4193 ◽

1997 ◽

Vol 124 (21) ◽

pp. 4193-4200 ◽

Cited By ~ 4

Author(s):

C. Wittmann ◽

O. Bossinger ◽

B. Goldstein ◽

M. Fleischmann ◽

R. Kohler ◽

...

Keyword(s):

Cell Fate ◽

Cell Polarity ◽

Hox Genes ◽

Positional Information ◽

Precursor Cell ◽

Body Parts ◽

Hox Gene ◽

C Elegans ◽

Fate Determinants ◽

Cell Fate Determinants

Clusters of homeobox-containing HOM-C/hox genes determine the morphology of animal body plans and body parts and are thought to mediate positional information. Here, we describe the onset of embryonic expression of ceh-13, the Caenorhabditis elegans orthologue of the Drosophila labial gene, which is the earliest gene of the C. elegans Hox gene cluster to be activated in C. elegans development. At the beginning of gastrulation, ceh-13 is asymmetrically expressed in posterior daughters of anteroposterior divisions, first in the posterior daughter of the intestinal precursor cell E and then in all posterior daughters of the AB descendants ABxxx. In this paper, we present evidence that supports position-independent activation of ceh-13 during early C. elegans embryogenesis, which integrates cell fate determinants and cell polarity cues. Our findings imply that mechanisms other than cell-extrinsic anteroposterior positional signals play an important role in the activation and regulation of the C. elegans Hox gene ceh-13.

Download Full-text