The bromodomain protein LIN-49 and trithorax-related protein LIN-59 affect development and gene expression in Caenorhabditis elegans

Development ◽  
2000 ◽  
Vol 127 (4) ◽  
pp. 713-723 ◽  
Author(s):  
H.M. Chamberlin ◽  
J.H. Thomas
Keyword(s):  
Gene Expression ◽  
Hox Genes ◽  
Structural Integrity ◽  
Egg Laying ◽  
Polycomb Group ◽  
Normal Morphology ◽  
Trithorax Group ◽  
Somatic Development ◽  
C Elegans ◽  
And Function

We have molecularly characterized the lin-49 and lin-59 genes in C. elegans, and found their products are related to Drosophila trithorax group (trx-G) proteins and other proteins implicated in chromatin remodelling. LIN-49 is structurally most similar to the human bromodomain protein BR140, and LIN-59 is most similar to the Drosophila trx-G protein ASH1. In C. elegans, lin-49 and lin-59 are required for the normal development of the mating structures of the adult male tail, for the normal morphology and function of hindgut (rectum) cells in both males and hermaphrodites and for the maintenance of structural integrity in the hindgut and egg-laying system in adults. Expression of the Hox genes egl-5 and mab-5 is reduced in lin-49 and lin-59 mutants, suggesting lin-49 and lin-59 regulate HOM-C gene expression in C. elegans as the trx-G genes do in Drosophila. lin-49 and lin-59 transgenes are expressed widely throughout C. elegans animals. Thus, in contrast to the C. elegans Polycomb group (Pc-G)-related genes mes-2 and mes-6 that function primarily in the germline, we propose lin-49 and lin-59 function in somatic development similar to the Drosophila trx-G genes.

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

Development ◽  
1999 ◽  
Vol 126 (1) ◽  
pp. 37-49 ◽  
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.

scholarly journals The transcriptional corepressor CTBP-1 acts with the SOX family transcription factor EGL-13 to maintain AIA interneuron cell identity in C. elegans

2021 ◽  
Author(s):  
Josh Saul ◽  
Takashi Hirose ◽  
Robert Horvitz
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Fate ◽  
Transcriptional Corepressor ◽  
Cell Identity ◽  
C Elegans ◽  
Dna Binding Specificity ◽  
A Cell ◽  
Transcriptional Corepressors ◽  
And Function

Cell identity is characterized by a distinct combination of gene expression, cell morphology and cellular function established as progenitor cells divide and differentiate. Following establishment, cell identities can be unstable and require active and continuous maintenance throughout the remaining life of a cell. Mechanisms underlying the maintenance of cell identities are incompletely understood. Here we show that the gene ctbp-1, which encodes the transcriptional corepressor C-terminal binding protein-1 (CTBP-1), is essential for the maintenance of the identities of the two AIA interneurons in the nematode Caenorhabditis elegans. ctbp-1 is not required for the establishment of the AIA cell fate but rather functions cell-autonomously and can act in older worms to maintain proper AIA gene expression, morphology and function. From a screen for suppressors of the ctbp-1 mutant phenotype, we identified the gene egl-13, which encodes a SOX family transcription factor. We found that egl-13 regulates AIA function and aspects of AIA gene expression, but not AIA morphology. We conclude that the CTBP-1 protein maintains AIA cell identity in part by utilizing EGL-13 to repress transcriptional activity in the AIAs. More generally, we propose that transcriptional corepressors like CTBP-1 might be critical factors in the maintenance of cell identities, harnessing the DNA-binding specificity of transcription factors like EGL-13 to selectively regulate gene expression in a cell-specific manner.

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

Development ◽  
1999 ◽  
Vol 126 (15) ◽  
pp. 3303-3312 ◽  
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.

The Polycomb group in Caenorhabditis elegans and maternal control of germline development

Development ◽  
1998 ◽  
Vol 125 (13) ◽  
pp. 2469-2478 ◽  
Author(s):  
I. Korf ◽  
Y. Fan ◽  
S. Strome
Keyword(s):  
Gene Expression ◽  
Caenorhabditis Elegans ◽  
Polycomb Group ◽  
Polycomb Group Proteins ◽  
Polycomb Group Protein ◽  
Maternal Control ◽  
Germline Development ◽  
C Elegans ◽  
Polycomb Group Genes ◽  
Group Protein

Four Caenorhabditis elegans genes, mes-2, mes-3, mes-4 and mes-6, are essential for normal proliferation and viability of the germline. Mutations in these genes cause a maternal-effect sterile (i.e. mes) or grandchildless phenotype. We report that the mes-6 gene is in an unusual operon, the second example of this type of operon in C. elegans, and encodes the nematode homolog of Extra sex combs, a WD-40 protein in the Polycomb group in Drosophila. mes-2 encodes another Polycomb group protein (see paper by Holdeman, R., Nehrt, S. and Strome, S. (1998). Development 125, 2457–2467). Consistent with the known role of Polycomb group proteins in regulating gene expression, MES-6 is a nuclear protein. It is enriched in the germline of larvae and adults and is present in all nuclei of early embryos. Molecular epistasis results predict that the MES proteins, like Polycomb group proteins in Drosophila, function as a complex to regulate gene expression. Database searches reveal that there are considerably fewer Polycomb group genes in C. elegans than in Drosophila or vertebrates, and our studies suggest that their primary function is in controlling gene expression in the germline and ensuring the survival and proliferation of that tissue.

Regulation of Hox Genes by Polycomb Group Protein EZH2 Plays a Critical Role in Diffuse Large B-Cell Lymphoma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1562-1562
Author(s):  
Irina Velichutina ◽  
Ari Melnick
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Target Genes ◽  
Hox Genes ◽  
Critical Role ◽  
Polycomb Group ◽  
Lymphoma Cells ◽  
Self Renewal ◽  
Hox Gene ◽  
Large B Cell

Abstract Coordinated regulation of Hox gene expression during hematopoiesis is epigenetically controlled via chromatin modification by Polycomb group (PcG) and Trithorax (MLL) protein complexes. Whereas the oncogenic potential of certain HOX genes in leukemia has already been defined, little is known about their role in Diffuse Large B-cell Lymphomas (DLBCL). The primary focus of our studies is to determine the contribution of PcG-mediated repression of HOX and other genes to DLBCL pathogenesis. The PcG protein, Ezh2, is vital for maintaining both pluripotency of stem cells and identity of differentiated cells. Ezh2 tri-methylates lysine K27 of histone 3 (H3K27me3), a histone modification associated with gene silencing. Importantly, Ezh2 is frequently overexpressed in DLBCLs suggesting a role for EZH2 in lymphomagenesis. In support to this notion we discovered that Ezh2 is essential for DLBCL cell survival. By depleting Ezh2 level using RNAi, we found that loss of Ezh2 triggers cell cycle arrest and death of DLBCL cells. This finding prompted us to initiate functional studies aimed at uncovering Ezh2 target genes that mediate the observed cellular response in DLBCL cells. We first focused on a potential role of Ezh2 in regulation of HOX genes. We compared and contrasted Ezh2 targets in both normal Germinal Center (GC) B-cells and GC-derived DLBCLs to determine the normal and pathologic function of EZH2. We employed a tiling ChIP-chip approach covering the four human HOX clusters and mapped Ezh2 and H3K27m3 within HOX gene clusters. We further verified gene expression status of a subset of Hox genes by QPCR. These data indicated that Ezh2 and its cognate H3K27m3 mark are present at promoters of HoxC genes in both mature GC B-cells and GC-derived lymphoma cells, thereby driving the HoxC locus silent, suggesting that both rapidly dividing GC cells and GC-derived lymphoma cells require epigenetic silencing of this locus in order to maintain their phenotype. Both Ezh2 and the corresponding H3K27m3 transcription repression mark are absent within the promoter region of HoxA9 gene. HoxA9 promotes stem cell self-renewal and it is aberrantly activated in AML cells. This observation is especially striking as the HoxA9 is embedded into the Ezh2-sealed region in DLBCL cells, suggesting an Ezh2-independent mode of regulation. We are in the process of testing functional significance of this finding for lymphoma pathogenesis. we found that HoxB genes that are differentially expressed in progenitor vs. lineage committed cells are silent in DLBCL cells according to H3K27m3/Ezh2 pattern and gene expression analysis. Intriguingly, the early progenitor specific gene, HoxB3, is uniquely not bound by EZH2 nor H3K27 methylated and was highly expressed in lymphoma cells. This finding underscores a potential functional significance of re-expression of genes that control cell self-renewal in malignances that derive from mature B cells. We also examined transcriptional programming by EZH2 at the genomic level by ChIP-on-chip using NimbleGen 24,000 promoter arrays. EZH2 was bound to ∼1700 promoters in DLBCL cells and a similar number of genes displayed H3K27 methylation. Gain and loss of function studies are underway to identify the contribution of the most likely EZH2 direct targets genes to the DLBCL survival including both HOX genes and other genomic direct target genes. Taken together, our data suggest a critical role for EZH2 mediated epigenetic silencing of HOX and other genes in DLBCL - and implicate aberrant HOX gene expression in DLBCL pathogenesis.

scholarly journals Molecular topography of an entire nervous system

2020 ◽  
Author(s):  
Seth R Taylor ◽  
Gabriel Santpere ◽  
Alexis Weinreb ◽  
Alec Barrett ◽  
Molly B. Reilly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Web Application ◽  
Gene Families ◽  
Regulatory Elements ◽  
Individual Neuron ◽  
Specific Gene ◽  
C Elegans ◽  
Underlying Mechanisms ◽  
And Function

SummaryNervous systems are constructed from a deep repertoire of neuron types but the underlying gene expression programs that specify individual neuron identities are poorly understood. To address this deficit, we have produced an expression profile of all 302 neurons of the C. elegans nervous system that matches the single cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses unique codes of ∼23 neuropeptide-encoding genes and ∼36 neuropeptide receptors thus pointing to an expansive “wireless” signaling network. To demonstrate the utility of this uniquely comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression across the nervous system and (2) reveal adhesion proteins with potential roles in synaptic specificity and process placement. These data are available at cengen.org and can be interrogated at the web application CengenApp. We expect that this neuron-specific directory of gene expression will spur investigations of underlying mechanisms that define anatomy, connectivity and function throughout the C. elegans nervous system.

Bimodal Degradation of MLL Protein by the Cell Cycle SCFSkp2 and APCCdc20 E3 Lilgases Assures Cell Cycle Execution: A Critical Regulatory Circuit Lost in Leukemogenic MLL-Fusions.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 828-828 ◽  
Author(s):  
Han Liu ◽  
David Chen ◽  
Todd Westergard ◽  
Shugaku Takeda ◽  
Satoru Sasagawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Hox Genes ◽  
S Phase ◽  
Polycomb Group ◽  
Cell Cycle Gene ◽  
E3 Ligases ◽  
M Phase ◽  
Phase Progression

Abstract The MLL (mixed lineage leukemia) gene encodes a highly conserved 3,969 aa histone H3 K4 methyl transferase, of which chromosome translocations result in poor prognostic infant and therapy-related leukemias. Mysteriously, the pathognomonic MLL leukemia fusions consist of a common amino(N)-terminal ∼1400 aa of MLL fused in frame with more than 60 different partners with no shared characteristics. The most well known genetic function of MLL is to antagonize polycomb group of proteins for proper Hox gene expression. Consequently deregulated Hox genes caused by MLL translocations contribute to the MLL leukemogenesis. Besides Hox genes, it remains largely undetermined whether MLL participates in other biological processes. The 500kD MLL precursor undergoes evolutionarily conserved proteolytic maturation mediated by Taspase1 (Hsieh et al. 2003, MCB, 23, 186–194; Hsieh et al. 2003, Cell, 115, 293–303). Our recent studies on Taspase1 knockout cells established an MLL-E2F axis in orchestrating core cell cycle gene expression including Cyclins and possibly Cdk inhibitors (Takeda et al. 2006, Genes & Development, 20, 2397–2409). As MLL actively participates in the cell cycle regulation, we investigated the regulation of MLL through cell cycle transition. We uncovered a unique biphasic expression of MLL conferred by defined windows of degradation mediated by specialized cell cycle E3 ligases. Specifically, SCFSkp2 and APCCdc20 mark MLL for degradation at S phase and late M phase, respectively. Abolished peak expression of MLL incurs corresponding defects in G1/S transition and M phase progression. Conversely, over-expression of MLL blocks S phase progression. Remarkably, MLL degradation initiates at its N-terminal ∼1400 aa that is retained in all MLL leukemia fusions. We examined prevalent MLL-fusions, including MLL-AF4, MLL-AF9, MLL-ELL and MLL-ELL, and observed their increased resistance to degradation. Furthermore, the same resistance was observed with the leukemogenic MLL-lacZ but not the non-leukemogenic MLL-Myc tag fusion. Thus, non-oscillating expression of MLL-fusions through the cell cycle, resulted from impaired degradation, likely constitutes the universal mechanism underlying all MLL leukemias. Our data conclude an essential post-translational regulation of MLL by the cell cycle ubiquitin/proteasome system (UPS) to assure the temporal necessity of MLL in coordinating cell cycle progression. Future studies aim at providing a comprehensive analysis on the cell cycle consequences associated with MLL-fusions using genetically modified cells derived from mice carrying various MLL-fusion knockin alleles, including MLL-AF4, MLL-AF9, and MLL-CBP.

scholarly journals Drosophila Hox genes induce melanized pseudo-tumors when misexpressed in hemocytes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Titus Ponrathnam ◽  
Ravina Saini ◽  
Sofia Banu ◽  
Rakesh K. Mishra
Keyword(s):  
Myeloid Leukemia ◽  
Hox Genes ◽  
Genetic Interaction ◽  
Cell Number ◽  
Polycomb Group ◽  
Trithorax Group ◽  
Proliferation And Differentiation ◽  
Group Members ◽  
Group Member ◽  
Anterior Posterior

AbstractHox genes are early determinants of cell identity along the anterior–posterior body axis across bilaterians. Several late non-homeotic functions of Hox genes have emerged in a variety of processes involved in organogenesis in several organisms, including mammals. Several studies have reported the misexpression of Hox genes in a variety of malignancies including acute myeloid leukemia. The Hox genes Dfd, Ubx, abd-A and Abd-B were overexpressed via the UAS-Gal4 system using Cg-Gal4, Lsp2-Gal4, He-Gal4 and HmlD3-Gal4 as specific drivers. Genetic interaction was tested by bringing overexpression lines in heterozygous mutant backgrounds of Polycomb and trithorax group factors. Larvae were visually scored for melanized bodies. Circulating hemocytes were quantified and tested for differentiation. Pupal lethality was assessed. Expression of Dfd, Ubx and abd-A, but not Abd-B in the hematopoietic compartment of Drosophila led to the appearance of circulating melanized bodies, an increase in cell number, cell-autonomous proliferation, and differentiation of hemocytes. Pupal lethality and melanized pseudo-tumors were suppressed in Psc1 and esc2 backgrounds while polycomb group member mutations Pc1 and Su(z)123 and trithorax group member mutation TrlR85 enhanced the phenotype. Dfd, Ubx and abd-A are leukemogenic. Mutations in Polycomb and trithorax group members modulate the leukemogenic phenotype. Our RNAseq of Cg-Gal4 > UAS-abd-A hemocytes may contain genes important to Hox gene induced leukemias.

scholarly journals Caenorhabditis elegans AF4/FMR2 family homolog affl-2 is required for heat shock induced gene expression

2019 ◽  
Author(s):  
Sophie J. Walton ◽  
Han Wang ◽  
Porfirio Quintero-Cadena ◽  
Alex Bateman ◽  
Paul W. Sternberg
Keyword(s):  
Gene Expression ◽  
Heat Stress ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Genetic Locus ◽  
Transcriptional Response ◽  
Egg Laying ◽  
Transcriptional Elongation ◽  
C Elegans ◽  
Shock Response

AbstractTo mitigate the deleterious effects of temperature increases on cellular organization and proteotoxicity, organisms have developed mechanisms to respond to heat stress. In eukaryotes, HSF1 is the master regulator of the heat shock transcriptional response, but the heat shock response pathway is not yet fully understood. From a forward genetic screen for suppressors of heat shock induced gene expression in C. elegans, we identified a new allele of hsf-1 that alters its DNA-binding domain, and three additional alleles of sup-45, a previously uncharacterized genetic locus. We identified sup-45 as one of the two hitherto unknown C. elegans orthologs of the human AF4/FMR2 family proteins, which are involved in regulation of transcriptional elongation rate. We thus renamed sup-45 as affl-2 (AF4/FMR2-Like). affl-2 mutants are egg-laying defective and dumpy, but worms lacking its sole paralog (affl-1) appear wild-type. AFFL-2 is a broadly expressed nuclear protein, and nuclear localization of AFFL-2 is necessary for its role in heat shock response. affl-2 and its paralog are not essential for proper HSF-1 expression and localization after heat shock, which suggests that affl-2 may function downstream or parallel of hsf-1. Our characterization of affl-2 provides insights into the complex processes of transcriptional elongation and regulating heat shock induced gene expression to protect against heat stress.

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