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

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.

scholarly journals Induction of HOX genes by HCV infection via impairment of histone H2A monoubiquitination.

2020 ◽  
pp. JVI.01784-20
Author(s):  
Hirotake Kasai ◽  
Kazuki Mochizuki ◽  
Tomohisa Tanaka ◽  
Atsuya Yamashita ◽  
Yoshiharu Matsuura ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Protein Expression ◽  
Hox Genes ◽  
Core Protein ◽  
Gene Promoter ◽  
Hcv Infection ◽  
Histone H2a ◽  
Hox Gene ◽  
The Core ◽  
Hcv Core Protein

Hepatitis C virus (HCV) infection causes liver pathologies, including hepatocellular carcinoma (HCC). Homeobox (HOX) gene products regulate embryonic development and are associated with tumorigenesis, although the regulation of HOX genes by HCV infection has not been clarified in detail. We examined the effect of HCV infection on HOX gene expression. In this study, HCV infection induced more than half of the HOX genes and reduced the level of histone H2A monoubiquitination on lysine (K) 119 (H2Aub), which represses HOX gene promoter activity. HCV infection also promoted proteasome-dependent degradation of RNF2, which is an E3 ligase mediating H2A monoubiquitination as a component of polycomb repressive complex 1. Since full-genomic replicon cells but not subgenomic replicon cells exhibited reduced RNF2 and H2Aub levels and induction of HOX genes, we focused on the core protein. Expression of the core protein reduced the amounts of RNF2 and H2Aub and induced HOX genes. Treatment with LY-411575, which can reduce HCV core protein expression via SPP inhibition without affecting other viral proteins, dose-dependently restored the amounts of RNF2 and H2Aub in HCV-infected cells and impaired the induction of HOX genes and production of viral particles but not viral replication. The chromatin immunoprecipitation assay results also indicated infection- and proteasome-dependent reductions in H2Aub located in HOX gene promoters. These results suggest that HCV infection or core protein induces HOX genes by impairing histone H2A monoubiquitination via a reduction in the RNF2 level.Importance Recently sustained virologic response can be achieved by direct acting antiviral therapy in most of hepatitis C patients. Unfortunately, DAA therapy does not completely eliminate a risk of HCC. Several epigenetic factors, including histone modifications, are well known to contribute to HCV-associated HCC. However, the regulation of histone modifications by HCV infection has not been clarified in detail. In this study, our data suggest that HCV infection or HCV core protein expression impairs monoubiquitination of histone H2A K119 in HOX gene promoter via destabilization of RNF2 and then induces HOX genes. Several lines of evidence suggest that the expression of several HOX genes is dysregulated in certain types of tumors. These findings reveal a novel mechanism of HCV-related histone modification and may provide information about new targets for diagnosis and prevention of HCC occurrence.

Comprehensive HOX Gene Expression Profiles Are Associated with Major Cytogenetic Prognostic Categories in AML.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2989-2989
Author(s):  
Harry A. Drabkin ◽  
Vivian Ruvolo ◽  
Sharvari Gadgil ◽  
Wenjing Chen ◽  
Chan Zeng ◽  
...  
Keyword(s):  
Cell Fate ◽  
Hox Genes ◽  
De Novo ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Model Systems ◽  
Acute Leukemias ◽  
Hox Gene ◽  
Cd34 Cells

Abstract The homeodomain genes comprise a set of transcription factors that determine cell fate by regulating proliferation, development, and apoptosis. Humans have 39 class I homeodomain genes (HOX) that occur in four clusters (HOXA, HOXB, HOXC, and HOXD). During development HOX expression takes place according to the position of a gene within its cluster and the position of the cell along the anterior - posterior axis. Some HOX genes are expressed in adult tissues, where they are thought to regulate the regenerative differentiation of cells. If one were to view leukemia as a disorder of regenerative hematopoesis, one could hypothesize that dysregulation of HOX expression promotes leukemogenesis. The role of some homeodomain genes in acute leukemia has been especially well studied. In mouse model systems, overexpression of HOXA7, HOXA9 and Meis1 lead to AML. Chromosomal translocations targeting HOX and other homeodomain genes are associated with acute myeloid and lymphoid leukemias. Previous results have suggested that HOX expression patterns might define certain AML subsets. In the present study, we analyzed the expression of 40 homeodomain genes, among them 25 of the HOXA-D genes, in leukemic enriched samples from 66 patients with de novo AML and in sorted CD34+ cells derived from four healthy bone marrow donors. Also, in order to integrate any effects of mutations in FLT3, C/EBPa, and nucleophosmin (NPM) on HOX expression, we assessed the presence of mutations in these three genes. Our results demonstrate that HOX expression patterns are intimately linked to particular cytogenetic abnormalities. The most striking overall findings were the overexpression of HOXA and HOXB genes in AMLs with NPM mutations, the similarity of HOX expression in AMLs with unfavorable cytogenetics to that of AMLs with intermediate cytogenetics, and the downregulation of HOXA genes in core binding factor (CBF) AMLs. Moreover, AMLs with translocations involving CBFbeta had distinctly higher expression of HOXB2, HOXB3, HOXB4, and Meis 1 than did patients with translocations involving CBFalpha. Some HOX genes displayed no heterogeneity of expression and are thus likely unrelated to leukemogenesis. Other genes, particularly HOXA and HOXB genes, displayed marked heterogeneity of expression and thus may have a role in leukemogenesis. However, every AML had substantial differences in the expression of at least one HOX gene compared to normal CD34+ cells. In addition, levels of HOX expression distinguished within individual cytogenetic groups certain subsets, including cases with inv(16) and cases that phenotypically resembled NPM mutations. Based on these results and the causative nature of HOX deregulation in some acute leukemias, we postulate that the HOX expression patterns exemplified here may be responsible for some (or many) of the biologic differences observed among the major cytogenetic prognostic groups.

Leukemic Pattern Of HOX Gene Expression Is Driven By Genetic Aberrations Through Epigenetic Modifiers

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2504-2504
Author(s):  
Julia Starkova ◽  
Karolina Kramarzova ◽  
Karel Fiser ◽  
Ester Mejstrikova ◽  
Katerina Rejlova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Pattern ◽  
Hox Genes ◽  
De Novo ◽  
In Vitro Experiments ◽  
Genetic Aberrations ◽  
Hox Gene ◽  
Epigenetic Modifiers ◽  
Fab Classification

Abstract Introduction Homeobox (HOX) genes encode transcription factors crucial in embryogenesis. They are often dysregulated in malignancies including leukemias. The aberrant HOX gene expression and its regulation in leukemic cells is neither completely described nor understood. Aims Our main aim was to determine whether the leukemic HOX gene expression pattern is driven by differentiation stage of hematopoietic cells or determined de novo during the process of malignant transformation. Consequentially, we aimed to study the role epigenetic modifiers in regulation of HOX gene expression in normal and malignant hematopoiesis. Methods The expression pattern of HOX genes (cluster of HOX A and B) and epigenetic modifiers (DNMT1, DNMT3a, DNMT3b, EZH2, BMI-1, MLL, JMJD3, UTX) was assessed by qPCR in 8 FACS-sorted subpopulations of healthy BM representing stages of myeloid differentiation (each sample representing a pool of cells sorted from five individuals). The leukemic expression pattern of these genes was analyzed in diagnostic BM samples of childhood AML patients with typical genotypic and morphological (FAB classification) characteristics (N=46). In vitro experiments were performed using NB4 cell line. Results As expected HOX genes were gradually downregulated during normal differentiation of granulocytic and monocytic lineages (assessed in four consecutive differentiation stages for each lineage). In AML samples, HOX gene expression patterns differed significantly among morphological subtypes. However, HOX gene expression did not correlate among subtypes of AML and their physiologically differentiated counterparts. Interestingly, unsupervised hierarchical clustering (HCA) divided AML patients into four main clusters characterized by the presence of prevalent gene rearrangement (PML-RARa, AML1-ETO, MLL rearrangements and NK-AML). The presence of PML/RARa rearrangement was strongly associated with the lowest expression of both HOXA and HOXB clusters, while the other groups had more variable expression of HOX genes. Moreover, the effect of genetic aberrations on HOX gene expression was clearly apparent within AML M2 and M4 subtypes, where AML1/ETO+ or CBFb/MYH11+ patients had significantly lower expression of HOX genes compared to patients with the same FAB classification but without the rearrangements. The expression pattern of epigenetic modifiers in sorted subpopulations of healthy BM followed their expected role in transcriptional regulation during differentiation. However, there was no relation of this pattern to HOX gene expression. On the contrary, in AML samples, the expression levels of epigenetic modifiers clearly correlated with expression profile of HOX genes. These results were supported by unsupervised HCA based on the expression of epigenetic modifiers that showed upregulation of histon demethylases JMJD3 and UTX together with downregulation of DNMT3b in concordance with high levels of HOX genes. Negative correlation between JMJD3 and DNMT3b expression was observed in all leukemic samples (p=0.03); most apparently in PML/RARa+ patients. Therefore we further studied the impact of genetic aberrations on the epigenetic regulation of HOX gene expression in vitrowith PML-RARa+ cell line. Treatment of NB4 cells with ATRA (8, 24hours, 1uM, 10uM) increased the levels of particular HOX genes (HOXA5, A7, B4, B7; FCA=2.8; 1.7; 4; 4 respectively) as well as JMJD3 (FCA=3) and UTX (FCA=1.6). Concordantly, the expression of DNMT3b (FCA=5) was downregulated. The hypothetical driving effect of PML-RARa on de novo determination of leukemic HOX gene expression is further supported by our Results. PML-RARa+ patients had the lowest HOX gene expression regardless of their FLT3/ITD status – previously shown to upregulate strongly HOX genes expression. Conclusion We conclude that the leukemic expression pattern of HOX genes does not reflect the differentiation stages of malignant cells. Our data also demonstrate different contribution of epigenetic modifiers to the HOX gene expression in healthy and malignant hematopoiesis. Moreover, HCA and expression data together with the results of in vitro experiments suggest that the specific molecular aberrations (as exemplified by PML-RARa) participate in regulation of leukemic HOX gene expression through epigenetic changes. Supported by GACR P304/12/2214, GAUK 568213, 00064203. Disclosures: No relevant conflicts of interest to declare.

A Green Fluorescent Protein Reporter Genetic Screen That Identifies Modifiers of Hox Gene Function in the Drosophila Embryo

Genetics ◽  
2002 ◽  
Vol 162 (1) ◽  
pp. 189-202 ◽  
Author(s):  
Samir Merabet ◽  
Francoise Catala ◽  
Jacques Pradel ◽  
Yacine Graba
Keyword(s):  
Gene Function ◽  
Target Genes ◽  
Hox Genes ◽  
Fluorescent Protein ◽  
Genetic Screen ◽  
Drosophila Embryo ◽  
Hox Gene ◽  
Gfp Fluorescence ◽  
Evolutionarily Conserved ◽  
Green Fluorescent

Abstract Hox genes encode evolutionarily conserved transcription factors that play fundamental roles in the organization of the animal body plan. Molecular studies emphasize that unidentified genes contribute to the control of Hox activity. In this study, we describe a genetic screen designed to identify functions required for the control of the wingless (wg) and empty spiracles (ems) target genes by the Hox Abdominal-A and Abdominal-B proteins. A collection of chromosomal deficiencies were screened for their ability to modify GFP fluorescence patterns driven by Hox response elements (HREs) from wg and ems. We found 15 deficiencies that modify the activity of the ems HRE and 18 that modify the activity of the wg HRE. Many deficiencies cause ectopic activity of the HREs, suggesting that spatial restriction of transcriptional activity is an important level in the control of Hox gene function. Further analysis identified eight loci involved in the homeotic regulation of wg or ems. A majority of these modifier genes correspond to previously characterized genes, although not for their roles in the regulation of Hox targets. Five of them encode products acting in or in connection with signal transduction pathways, which suggests an extensive use of signaling in the control of Hox gene function.

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

Development ◽  
1998 ◽  
Vol 125 (24) ◽  
pp. 4949-4957 ◽  
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.

The evolving role of Hox genes in arthropods

Development ◽  
1994 ◽  
Vol 1994 (Supplement) ◽  
pp. 209-215
Author(s):  
Michael Akam ◽  
Michalis Averof ◽  
James Castelli-Gair ◽  
Rachel Dawes ◽  
Francesco Falciani ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Early Development ◽  
Hox Genes ◽  
Homeotic Gene ◽  
Homeotic Genes ◽  
Gene Duplications ◽  
Fushi Tarazu ◽  
Hox Gene ◽  
Hox Cluster

Comparisons between Hox genes in different arthropods suggest that the diversity of Antennapedia-class homeotic genes present in modern insects had already arisen before the divergence of insects and crustaceans, probably during the Cambrian. Hox gene duplications are therefore unlikely to have occurred concomitantly with trunk segment diversification in the lineage leading to insects. Available data suggest that domains of homeotic gene expression are also generally conserved among insects, but changes in Hox gene regulation may have played a significant role in segment diversification. Differences that have been documented alter specific aspects of Hox gene regulation within segments and correlate with alterations in segment morphology rather than overt homeotic transformations. The Drosophila Hox cluster contains several homeobox genes that are not homeotic genes – bicoid, fushi-tarazu and zen. The role of these genes during early development has been studied in some detail. It appears to be without parallel among the vertebrate Hox genes. No well conserved homologues of these genes have been found in other taxa, suggesting that they are evolving faster than the homeotic genes. Relatively divergent Antp-class genes isolated from other insects are probably homologues of fushi-tarazu, but these are almost unrecognisable outside of their homeodomains, and have accumulated approximately 10 times as many changes in their homeodomains as have homeotic genes in the same comparisons. They show conserved patterns of expression in the nervous system, but not during early development.

scholarly journals 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

2021 ◽  
Author(s):  
John Isaac Murray ◽  
Elicia Preston ◽  
Jeremy P. Crawford ◽  
Jonathan D. Rumley ◽  
Prativa Amom ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Cell Division ◽  
Hox Genes ◽  
Hox Gene ◽  
Animal Development ◽  
C Elegans ◽  
Transcriptional Enhancers ◽  
Positional Identity ◽  
Cell Position ◽  
And Function

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.

scholarly journals Structural catalog of core Atg proteins opens new era of autophagy research

2021 ◽  
Author(s):  
Kazuaki Matoba ◽  
Nobuo N Noda
Keyword(s):  
De Novo ◽  
Structural Information ◽  
Membrane Dynamics ◽  
Autophagosome Formation ◽  
New Era ◽  
Intracellular Degradation ◽  
Atg Proteins ◽  
Biological Studies ◽  
Evolutionarily Conserved ◽  
Biological Methods

Summary Autophagy, which is an evolutionarily conserved intracellular degradation system, involves de novo generation of autophagosomes that sequester and deliver diverse cytoplasmic materials to the lysosome for degradation. Autophagosome formation is mediated by approximately 20 core autophagy-related (Atg) proteins, which collaborate to mediate complicated membrane dynamics during autophagy. To elucidate the molecular functions of these Atg proteins in autophagosome formation, many researchers have tried to determine the structures of Atg proteins by using various structural biological methods. Although not sufficient, the basic structural catalog of all core Atg proteins was established. In this review article, we summarize structural biological studies of core Atg proteins, with an emphasis on recently unveiled structures, and describe the mechanistic breakthroughs in autophagy research that have derived from new structural information.

scholarly journals Hox genes are essential for the development of eyespots in Bicyclus anynana butterflies

Genetics ◽  
2020 ◽  
Vol 217 (1) ◽  
Author(s):  
Yuji Matsuoka ◽  
Antónia Monteiro
Keyword(s):  
Hox Genes ◽  
Bicyclus Anynana ◽  
Hox Gene ◽  
Novel Traits ◽  
Anterior Posterior ◽  
Anterior Posterior Axis

Abstract The eyespot patterns found on the wings of nymphalid butterflies are novel traits that originated first in hindwings and subsequently in forewings, suggesting that eyespot development might be dependent on Hox genes. Hindwings differ from forewings in the expression of Ultrabithorax (Ubx), but the function of this Hox gene in eyespot development as well as that of another Hox gene Antennapedia (Antp), expressed specifically in eyespots centers on both wings, are still unclear. We used CRISPR-Cas9 to target both genes in Bicyclus anynana butterflies. We show that Antp is essential for eyespot development on the forewings and for the differentiation of white centers and larger eyespots on hindwings, whereas Ubx is essential not only for the development of at least some hindwing eyespots but also for repressing the size of other eyespots. Additionally, Antp is essential for the development of silver scales in male wings. In summary, Antp and Ubx, in addition to their conserved roles in modifying serially homologous segments along the anterior–posterior axis of insects, have acquired a novel role in promoting the development of a new set of serial homologs, the eyespot patterns, in both forewings (Antp) and hindwings (Antp and Ubx) of B. anynana butterflies. We propose that the peculiar pattern of eyespot origins on hindwings first, followed by forewings, could be due to an initial co-option of Ubx into eyespot development followed by a later, partially redundant, co-option of Antp into the same network.

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