scholarly journals Gsx2 but not Gsx1 is necessary for early forebrain patterning and long-term survival in zebrafish

2021 ◽  
Author(s):  
RA Coltogirone ◽  
EI Sherfinski ◽  
ZA Dobler ◽  
SN Peterson ◽  
AR Andlinger ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Networks ◽  
Target Genes ◽  
Molecular Genetic ◽  
Brain Regions ◽  
Transcription Activator ◽  
Term Survival ◽  
Altered Expression ◽  
Larval Stages

ABSTRACTCentral nervous system (CNS) development is regulated by regionally expressed transcription factors that impart initial cell identity, connectivity, and function to neural circuits through complex molecular genetic cascades. genomic screen homeobox 1 and 2 (gsx1 and gsx2) encode homeobox transcription factors expressed in the developing CNS in multiple vertebrates examined to date. However, we have limited knowledge of the expression of these transcription factors and the gene networks that they regulate across developing brain regions in zebrafish. The objective of this study was to comprehensively examine gsx1 and gsx2 expression throughout neurodevelopment and characterize gsx1 and gsx2 mutants to study the essential roles of these closely related transcription factors. Using RT-PCR, whole-mount in situ hybridization (WISH), and fluorescence in situ hybridization, we examine gsx1 and gsx2 expression from early embryonic to late larval stages. gsx1 is expressed initially in the hindbrain and diencephalon and later in the optic tectum, pretectum, and cerebellar plate. Comparatively, gsx2 is expressed in the early telencephalon and later in the pallium and olfactory bulb. gsx1 and gsx2 are regionally co-expressed in the hypothalamus, preoptic area, and hindbrain, however rarely co-localize in the same cells. To identify forebrain target genes, we utilize mutants made with Transcription activator-like effector nucleases (TALEN). gsx1 mutant zebrafish exhibit stunted growth, however, they survive through adulthood and are fertile. gsx2 mutant zebrafish experience swim bladder inflation failure that prevents survival past larval stage. Using WISH and RT-qPCR we demonstrate altered expression of genes including, distal-less homeobox genes and forkhead box gene foxp2. This work provides novel tools with which other target genes and functions of Gsx1 and Gsx2 can be characterized across the CNS to better understand the unique and overlapping roles of these highly conserved transcription factors.

scholarly journals Differential developmental expression of transcription factors GATA-4 and GATA-6, their cofactor FOG-2 and downstream target genes in testicular carcinoma in situ and germ cell tumors

2010 ◽  
Vol 162 (3) ◽  
pp. 625-631 ◽  
Author(s):  
Jonna Salonen ◽  
Ewa Rajpert-De Meyts ◽  
Susanna Mannisto ◽  
John E Nielsen ◽  
Niels Graem ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Germ Cell ◽  
Germ Cells ◽  
Target Genes ◽  
Developmental Expression ◽  
Human Testis ◽  
Testicular Development ◽  
Downstream Target ◽  
Germ Cell Differentiation

ObjectiveTesticular germ cell cancer is the most common malignancy among young males. The pre-invasive precursor, carcinoma in situ testis (CIS), presumably originates from arrested and transformed fetal gonocytes. Given that GATA transcription factors have essential roles in embryonic and testicular development, we explored the expression of GATA-4, GATA-6, cofactor friend of GATA (FOG)-2, and downstream target genes during human testis development and addressed the question whether changes in this pathway may contribute to germ cell neoplasms.MethodsFetal testis, testicular CIS, and overt tumor samples were analyzed by immunohistochemistry for GATA-4, GATA-6, FOG-2, steroidogenic factor 1 (NR5A1/SF1), anti-Müllerian hormone/Müllerian-inhibiting substance (AMH), and inhibin-α (INHα).ResultsGATA-4 was not expressed in normal germ cells, except for a subset of gonocytes at the 15th gestational week. The CIS cells expressed GATA-4 and GATA-6 heterogeneously, whereas most of the CIS cells expressed GATA-4 cofactor FOG-2. GATA target gene SF-1 was expressed heterogeneously in CIS cells, whereas INHα and AMH were mostly negative. Seminomas and yolk sac tumors were positive for GATA-4 and GATA-6, but mostly negative for FOG-2 and the GATA target genes. In contrast, pluripotent embryonal carcinomas and choriocarcinomas were GATA-4 and GATA-6 negative.ConclusionsDifferential expression of the GATA-4 target genes suggested cell-specific functions of GATA-4 in the germ and somatic cells. The GATA-4 expression in early fetal gonocytes, CIS, and seminoma cells but the absence in more mature germ cells is consistent with the early fetal origin of CIS cells and suggests that GATA-4 is involved in early germ cell differentiation.

scholarly journals Dominant Negative Autoregulation Limits Steady-State Repression Levels in Gene Networks

2009 ◽  
Vol 191 (14) ◽  
pp. 4487-4491 ◽  
Author(s):  
Szabolcs Semsey ◽  
Sandeep Krishna ◽  
János Erdőssy ◽  
Péter Horváth ◽  
László Orosz ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Networks ◽  
Target Genes ◽  
Regulatory Protein ◽  
Dominant Negative ◽  
State Repression ◽  
Protein Levels ◽  
Environmental Transitions ◽  
Negative Autoregulation ◽  
Cell Variation

ABSTRACT Many transcription factors repress transcription of their own genes. Negative autoregulation has been shown to reduce cell-cell variation in regulatory protein levels and speed up the response time in gene networks. In this work we examined transcription regulation of the galS gene and the function of its product, the GalS protein. We observed a unique operator preference of the GalS protein characterized by dominant negative autoregulation. We show that this pattern of regulation limits the repression level of the target genes in steady states. We suggest that transcription factors with dominant negative autoregulation are designed for regulating gene expression during environmental transitions.

scholarly journals Functional Interrogation of Enhancer Connectome Prioritizes Candidate Target Genes at Ovarian Cancer Susceptibility Loci

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Wang ◽  
Fengju Song ◽  
Xiangling Feng ◽  
Xinlei Chu ◽  
Hongji Dai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Resolution ◽  
Gene Networks ◽  
Target Genes ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Contact Map ◽  
Altered Expression ◽  
Regulatory Variants ◽  
Causal Variants

Identifying causal regulatory variants and their target genes from the majority of non-coding disease-associated genetic loci is the main challenge in post-Genome-Wide Association Studies (GWAS) functional studies. Although chromosome conformation capture (3C) and its derivative technologies have been successfully applied to nominate putative causal genes for non-coding variants, many GWAS target genes have not been identified yet. This study generated a high-resolution contact map from epithelial ovarian cancer (EOC) cells with two H3K27ac-HiChIP libraries and analyzed the underlying gene networks for 15 risk loci identified from the largest EOC GWAS. By combinatory analysis of 4,021 fine-mapped credible variants of EOC GWAS and high-resolution contact map, we obtained 162 target genes that mainly enriched in cancer related pathways. Compared with GTEx eQTL genes in ovarian tissue and annotated proximal genes, 132 HiChIP targets were first identified for EOC causal variants. More than half of the credible variants (CVs) involved interactions that were over 185 kb in distance, indicating that long-range transcriptional regulation is an important mechanism for the function of GWAS variants in EOC. We also found that many HiChIP gene targets showed significantly differential expressions between normal ovarian and EOC tumor samples. We validated one of these targets by manipulating the rs9303542 located region with CRISPR-Cas9 deletion and dCas9-VP64 activation experiments and found altered expression of HOXB7 and HOXB8 at 17q21.32. This study presents a systematic analysis to identify putative target genes for causal variants of EOC, providing an in-depth investigation of the mechanisms of non-coding regulatory variants in the etiology and pathogenesis of ovarian cancer.

scholarly journals Divergent Targets of Aspergillus fumigatus AcuK and AcuM Transcription Factors during GrowthIn Vitroversus Invasive Disease

2014 ◽  
Vol 83 (3) ◽  
pp. 923-933 ◽  
Author(s):  
Monsicha Pongpom ◽  
Hong Liu ◽  
Wenjie Xu ◽  
Brendan D. Snarr ◽  
Donald C. Sheppard ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Aspergillus Fumigatus ◽  
Target Genes ◽  
Iron Acquisition ◽  
Altered Expression ◽  
Content Type ◽  
Regulatory Pathways ◽  
Transcriptional Profiles

InAspergillus nidulans, the AcuK and AcuM transcription factors form a complex that regulates gluconeogenesis. InAspergillus fumigatus, AcuM governs gluconeogenesis and iron acquisitionin vitroand virulence in immunosuppressed mice. However, the function of AcuK was previously unknown. Throughin vitrostudies, we found thatA. fumigatusΔacuKsingle and ΔacuKΔacuMdouble mutants had impaired gluconeogenesis and iron acquisition, similar to the ΔacuMmutant. Also, the ΔacuK, ΔacuM, and ΔacuKΔacuMmutants had similar virulence defects in mice. However, the ΔacuKmutant had a milder defect in extracellular siderophore activity and induction of epithelial cell damagein vitrothan did the ΔacuMmutant. Moreover, overexpression ofacuMin the ΔacuKmutant altered expression of 3 genes and partially restored growth under iron-limited conditions, suggesting that AcuM can govern some genes independently of AcuK. Although the ΔacuKand ΔacuMmutants had very similar transcriptional profilesin vitro, their transcriptional profiles during murine pulmonary infection differed both from theirin vitroprofiles and from each other. While AcuK and AcuM governed the expression of only a few iron-responsive genesin vivo, they influenced the expression of other virulence-related genes, such ashexAanddvrA. Therefore, inA. fumigatus, while AcuK and AcuM likely function as part of the same complex, they can also function independently of each other. Furthermore, AcuK and AcuM have different target genesin vivothanin vitro, suggesting thatin vivoinfection stimulates unique transcriptional regulatory pathways inA. fumigatus.

Regulation of Myelopoiesis by Differentiation Stage-Specific Activities of HOXA9 and HOXA10

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-29-SCI-29
Author(s):  
Elizabeth A. Eklund
Keyword(s):  
Bone Marrow ◽  
Transcription Factors ◽  
Gene Networks ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Murine Bone Marrow

Abstract Abstract SCI-29 HOXA9 and HOXA10 are homeodomain (HD) transcription factors that are implicated in control of myelopoiesis and contribute to myeloid leukemogenesis. These proteins are expressed coordinately during hematopoiesis, with maximal expression in granulocyte/monocyte progenitor (GMP) cells. Engineered overexpression of Hoxa9 or Hoxa10 in primary bone marrow cells expands the GMP population in vitro, and results in myeloproliferation in murine bone marrow transplant experiments. Mice transplanted with Hoxa9- or Hoxa10-overexpressing bone marrow develop acute myeloid leukemia (AML) over time. Consistent with this, increased and sustained expression of a set of HD proteins, including HOXA9 and HOXA10, is found in a subset of human AML, including AML with MLL gene translocations (11q23-AML). Since the DNA-binding HDs of HOXA9 and HOXA10 are highly conserved, we hypothesize that they recognize a common set of target genes. However, since HOXA9 and HOXA10 diverge outside the HD, we considered the unexplored possibility that they perform different functions in regulating such genes. To identify molecular mechanisms for HOX-induced GMP expansion and leukemogenesis, we performed a chromatin immunoprecipitation-based screen for HOXA10 target genes. Gene ontology studies determined that the identified set is enriched for genes encoding growth factors and receptors, including fibroblast growth factor 2 (FGF2). We found that production of FGF2 by Hoxa10-overexpressing GMP stabilizes β-catenin and induces proliferation in an autocrine manner. We also found that HOXA9 and HOXA10 activate common FGF2 cis elements. The Hoxa10-target-gene set is also enriched for HD-transcription factors, including CDX4. We determined that Cdx4 transcription is activated by HOXA10 in GMP, but repressed by HOXA9 in differentiating myeloid cells. CDX4 activates transcription of both Hoxa9 and Hoxa10, identifying a HOX-CDX cross-regulatory mechanism. This mechanism may be influenced by Fgf2, since Hoxa10 and Cdx4 are β-catenin target genes, but β-catenin activity decreases Hoxa9 expression. Gene expression profiling studies indicate that HOXA9, HOXA10, CDX4, and FGF2 are increased in 11q23-AML, suggesting clinical relevance. Arih2 (encoding the E3 ligase Triad1) is another common HOXA9 and HOXA10 target gene that may influence Fgf2 activity. We found that Arih2 transcription is repressed by HOXA9 in myeloid progenitors, but activated by HOXA10 in differentiating phagocytes. FGF receptors are destabilized by ubiquitination, and we found increased FGF-R ubiquitination in Hoxa10-overexpressing cells. Therefore, Triad1-dependent regulation of FGF-R stability is another mechanism for control of FGF2 activity and myeloproliferation by HOXA9 and HOXA10. Therefore, HOXA9 and HOXA10 regulate a common set of target genes that control GMP expansion in a manner that is antagonistic for some genes and cooperative for others. Clinical correlative studies suggest that coordinate control of these genes by HOXA9 and HOXA10 is dysregulated in HOX-overexpressing leukemia. Understanding HOX-regulated gene networks may identify therapeutic targets for HOX-overexpressing leukemias. For example, blocking FGF-related signaling pathways may ameliorate cytokine hypersensitivity in such leukemias, and would be a topic of interest for additional studies. Disclosures: No relevant conflicts of interest to declare.

Comprehensive Network Analysis of the Molecular Mechanisms Associated with Sorafenib Resistance in Hepatocellular Carcinoma

2019 ◽  
Author(s):  
Xiang Cui ◽  
Chao Li ◽  
Chunshan Wei ◽  
Guangdong Tong ◽  
Yufeng Xing
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factors ◽  
Differentially Expressed Genes ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Differential Expression Analysis ◽  
Diagnostic Value ◽  
The Body ◽  
Differentially Expressed

Abstract Background: This research aimed to investigate the potential molecular mechanism of sorafenib resistance to hepatocellular carcinoma (HCC). Methods: Differential expression analysis were performed to identified differentially expressed genes (DEGs) in sorafenib resistant HCC. Then, a series of bioinformatic analysis were performed to explore the potential crucial molecules in sorafenib resistant HCC. For example, gene function annotation, pivot regulators prediction, ROC analysis and survival analysis. Results: There were 827 differentially expressed genes were identified. Moreover, most of the differentially expressed genes are involved in immune and inflammatory-related functions and signaling pathways. Also, 18 transcription factors were predicted to regulate the transcription factors of differentially expressed genes, which play an essential role in the regulation of dysfunctional gene networks. In target genes of transcription factors, CDK1 and CDKN1A have high diagnostic value in the resistance of hepatocellular carcinoma to sorafenib. Conclusions: TAPBP has the strongest correlation with drug resistance of hepatocellular carcinoma and the highest diagnostic efficiency. In addition, CDK1 and CDKN1A have high diagnostic value in the resistance of hepatocellular carcinoma to sorafenib. Overall, our analysis shows that a large number of gene disorders occur during the development of resistance to sorafenib in hepatocellular carcinoma, and they are associated with immune and inflammatory reactions in the body. These results provide critical theoretical references for the pathogenesis and diagnosis of sorafenib resistance.

scholarly journals An Analysis of the Implication of Estrogens and Steroid Receptor Coactivators in the Genetic Basis of Gender Incongruence

2021 ◽  
Author(s):  
Rosa Fernández ◽  
Karla Ramírez ◽  
Enrique Delgado-Zayas ◽  
Esther Gómez-Gil ◽  
Isabel Esteva ◽  
...  
Keyword(s):  
Sex Differences ◽  
Transcription Factors ◽  
Target Genes ◽  
Intimate Relationship ◽  
Brain Regions ◽  
Adult Brain ◽  
Neuronal Function ◽  
Cascade Effect ◽  
Steroid Receptor Coactivators ◽  
The Brain

In mammals, sex differences in the adult brain are established very early in development, when the brain is still very immature. In the case of having inherited the SRY gene, during embryogenesis, testosterone secreted by the testes enters the brain and is converted to estradiol by the aromatase. Then the estradiol acts by binding to intracellular estrogen receptors (ERs) located predominantly in neurons, masculinizing specific brain regions. But ERs are also transcription factors that, when they are exposed to their ligand, dimerize and form complexes with coactivator proteins and corepressors, modifying the transcription of multiple target genes in a cascade effect and ultimately neuronal function. Given the intimate relationship between steroids and brain dimorphism, and steroid coactivators and gene transcription, in the present work, we further explore the implication of ERs α and β, and steroid coactivators NCoA-1, NCoA-2, NCoA-3, NCoA-4, NCoA-5 and p300-CREBBP, in the genesis of brain dimorphism. Based on our data, we believe that the coactivators NCOA-1, NCOA-2 and p300-CREBBP could be considered as candidate genes for GI.

Enhancer-Promoter Looping Deciphers Dosage of the Haploinsufficient Transcription Factor, CUX1

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2700-2700
Author(s):  
Robert K Arthur ◽  
Ningfei An ◽  
Saira Kahn ◽  
Megan E. McNerney
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
Binding Sites ◽  
Tumor Suppressor Genes ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Suppressor Genes ◽  
Major Barrier ◽  
Altered Expression

Abstract One third of tumor suppressor genes encode haploinsufficient transcriptional regulators, including transcription factors and chromatin remodelers. This presents a major barrier in oncology, as tumor suppressor genes and transcription factors are inherently difficult to target therapeutically. It remains unknown how a 50% reduction of a transcriptional regulator translates at the cis-regulatory level into a malignant transcriptional program. It is imperative to address this question, in order to predict and target aberrant downstream pathways. CUX1 encodes a quintessential haploinsufficient transcription factor that is recurrently mutated or deleted, monoallelically, in high-risk myeloid neoplasms and across solid tumor types. We hypothesized that the transcriptional response to changes in CUX1 level is encoded within the cis-regulatory architecture of dosage-sensitive CUX1 target genes. In this study, we determined that CUX1 primarily binds distal enhancers, in a tissue-specific manner. CUX1 binding sites are significantly enriched for co-binding with transcriptional activators and cohesin components. Haploinsufficiency of CUX1 in K562 myeloid leukemia cells led to altered expression of mitotic and apoptotic genes with concomitant increased cellular proliferation. Surprisingly, ChIP-seq of CUX1 in the haploinsufficient state revealed a unimodal decrease in CUX1 occupancy genome-wide, with no relevance to differential gene expression. Thus we used a machine-learning algorithm to identify characteristics of CUX1 binding sites at dosage-sensitive target genes and revealed a relationship with distance to the transcription start site, chromatin accessibility, and enhancer activity. Finally, we demonstrate that CUX1 binding sites at dosage-sensitive genes loop to the promoter, and those genes with an intermediate number of Hi-C loops are most responsive to changes in CUX1 abundance. Overall, these data point to a novel mechanism of transcription factor dose-responsiveness mediated by enhancer-promoter looping. Disclosures No relevant conflicts of interest to declare.

MicroRNAs and their role in hematological malignant diseases

2012 ◽  
Vol 153 (52) ◽  
pp. 2051-2059 ◽  
Author(s):  
Zsuzsanna Gaál ◽  
Éva Oláh
Keyword(s):  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Cancer Tissue ◽  
Altered Expression ◽  
Diagnosis And Prognosis ◽  
Oncologic Patients ◽  
Different Types ◽  
Non Coding Rnas ◽  
Success Of Treatment ◽  
Posttranscriptional Level

MicroRNAs are a class of small non-coding RNAs regulating gene expression at posttranscriptional level. Their target genes include numerous regulators of cell cycle, cell proliferation as well as apoptosis. Therefore, they are implicated in the initiation and progression of cancer, tissue invasion and metastasis formation as well. MicroRNA profiles supply much information about both the origin and the differentiation state of tumours. MicroRNAs also have a key role during haemopoiesis. An altered expression level of those have often been observed in different types of leukemia. There are successful attempts to apply microRNAs in the diagnosis and prognosis of acute lymphoblastic leukemia and acute myeloid leukemia. Measurement of the expression levels may help to predict the success of treatment with different kinds of chemotherapeutic drugs. MicroRNAs are also regarded as promising therapeutic targets, and can contribute to a more personalized therapeutic approach in haemato-oncologic patients. Orv. Hetil., 2012, 153, 2051–2059.

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