scholarly journals JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

2017 ◽  
Author(s):  
Lusy Handoko ◽  
Bogumil Kaczkowski ◽  
Chung-Chau Hon ◽  
Marina Lizio ◽  
Masatoshi Wakamori ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Nsclc Cell Line ◽  
Histone H4 ◽  
Transcription Start ◽  
Independent Manner ◽  
Downstream Target ◽  
Genome Wide ◽  
Integrative Analyses ◽  
Bet Protein

ABSTRACTThe bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Interestingly, although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed. In addition, a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and independent manner.

Drosophila Gain-of-Function Mutant RTK Torso Triggers Ectopic Dpp and STAT Signaling

Genetics ◽  
2003 ◽  
Vol 164 (1) ◽  
pp. 247-258 ◽  
Author(s):  
Jinghong Li ◽  
Willis X Li
Keyword(s):  
Tyrosine Kinases ◽  
Target Genes ◽  
Tor Signaling ◽  
Gain Of Function ◽  
Essential Requirement ◽  
Downstream Target ◽  
Rtk Signaling ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Regions

Abstract Overactivation of receptor tyrosine kinases (RTKs) has been linked to tumorigenesis. To understand how a hyperactivated RTK functions differently from wild-type RTK, we conducted a genome-wide systematic survey for genes that are required for signaling by a gain-of-function mutant Drosophila RTK Torso (Tor). We screened chromosomal deficiencies for suppression of a gain-of-function mutation tor (torGOF), which led to the identification of 26 genomic regions that, when in half dosage, suppressed the defects caused by torGOF. Testing of candidate genes in these regions revealed many genes known to be involved in Tor signaling (such as those encoding the Ras-MAPK cassette, adaptor and structural molecules of RTK signaling, and downstream target genes of Tor), confirming the specificity of this genetic screen. Importantly, this screen also identified components of the TGFβ (Dpp) and JAK/STAT pathways as being required for TorGOF signaling. Specifically, we found that reducing the dosage of thickveins (tkv), Mothers against dpp (Mad), or STAT92E (aka marelle), respectively, suppressed torGOF phenotypes. Furthermore, we demonstrate that in torGOF embryos, dpp is ectopically expressed and thus may contribute to the patterning defects. These results demonstrate an essential requirement of noncanonical signaling pathways for a persistently activated RTK to cause pathological defects in an organism.

scholarly journals Genome-Wide Dynamics of SAPHIRE, an Essential Complex for Gene Activation and Chromatin Boundaries

2007 ◽  
Vol 27 (11) ◽  
pp. 4058-4069 ◽  
Author(s):  
Matthew Gordon ◽  
Derick G. Holt ◽  
Anil Panigrahi ◽  
Brian T. Wilhelm ◽  
Hediye Erdjument-Bromage ◽  
...  
Keyword(s):  
Target Genes ◽  
Gene Activation ◽  
Histone Demethylase ◽  
Ribosomal Protein Genes ◽  
Transcription Start ◽  
Highly Active ◽  
Enzymatic Function ◽  
Genome Wide ◽  
Boundary Regulation ◽  
Nucleosome Binding

ABSTRACT In this study, we characterize a four-protein nucleosome-binding complex from Schizosaccharomyces pombe, termed SAPHIRE, that includes two orthologs of human Lsd1, a histone demethylase. The SAPHIRE complex is essential for cell viability, whereas saphire mutants lacking key conserved catalytic residues are viable but thermosensitive, suggesting that SAPHIRE has both an important enzymatic function and an essential nonenzymatic function. SAPHIRE is present in (or adjacent to) particular heterochromatic loci and also in the transcription start site regions of many highly active polymerase II genes. However, ribosomal protein genes are notably SAPHIRE deficient. SAPHIRE promotes activation, as target genes are selectively attenuated in saphire mutants. Interestingly, saphire mutants display increased histone H3 lysine 4 dimethylation, a modification typically associated with euchromatin. SAPHIRE localization is dynamic, as activated genes rapidly acquire SAPHIRE. Furthermore, saphire mutants dramatically shift a heterochromatin-euchromatin boundary in Chr1, suggesting a novel role in boundary regulation.

HPV-associated penile cancer: Impact of copy number alterations in miRNA/mRNA interactions and potential druggable targets

2021 ◽  
pp. 1-14
Author(s):  
Jenilson da Silva ◽  
Leudivan Nogueira ◽  
Ronald Coelho ◽  
Amanda Deus ◽  
André Khayat ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Copy Number ◽  
Drug Targets ◽  
Penile Cancer ◽  
Target Genes ◽  
Kegg Pathways ◽  
Mrna Targets ◽  
Genome Wide ◽  
Target Treatment ◽  
Druggable Targets

BACKGROUND: Penile cancer (PeCa) is a rare disease, but its incidence has increased worldwide, mostly in HPV+ patients. Nevertheless, there is still no targeted treatment for this carcinoma. OBJECTIVE: To predict the main signaling pathways involved in penile tumorigenesis and its potential drug targets. METHODS: Genome-wide copy number profiling was performed in 28 PeCa. Integration analysis of CNAs and miRNAs and mRNA targets was performed by DIANA-TarBase v.8. The potential impact of the miRNAs/target genes on biological pathways was assessed by DIANA-miRPath v.3.0. For each miRNA, KEGG pathways were generated based on the tarbase and microT-CDS algorithms. Pharmaco-miR was used to identify associations between miRNAs and their target genes to predict druggable targets. RESULTS: 269 miRNAs and 2,395 genes were mapped in cytobands with CNAs. The comparison of the miRNAs mapped at these cytobands and the miRNAs that were predicted to regulate the genes also mapped in these regions, resulted in a set of common 35 miRNAs and 292 genes. Enrichment pathway revealed their involvement in five top signaling pathways. EGFR and COX2 were identified as potential druggable targets. CONCLUSION: Our data indicate the potential use of EGFR and COX2 inhibitors as a target treatment for PeCa patients.

scholarly journals VHLSynthetic Lethality Signatures Uncovered by Genotype-specific CRISPR-Cas9 Screens

2019 ◽  
Author(s):  
Ning Sun ◽  
Sakina Petiwala ◽  
Charles Lu ◽  
Jessica E Hutti ◽  
Min Hu ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Drug Targets ◽  
Target Genes ◽  
Synthetic Lethality ◽  
Suppressor Gene ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Genome Wide ◽  
Tumor Suppressor Gene Inactivation

AbstractBackgroundGenome-wide CRISPR-Cas9 essentiality screening represents a powerful approach to identify genetic vulnerabilities in cancer cells. Here, we applied this technology and designed a strategy to identify target genes that are synthetic lethal (SL) withvon Hippel-Lindau(VHL) tumor suppressor gene. Inactivation ofVHLhas been frequently found in clear cell renal cell carcinoma (ccRCC). Its SL partners serve as potential drug targets for the development of targeted cancer therapies.ResultsWe performed parallel genome-wide CRISPR screens in two pairs of isogenic ccRCC cell lines that differ only in theVHLstatus. Comparative analyses of screening results not only confirmed a well-known role for mTOR signaling in renal carcinoma, but also identified DNA damage response and selenocysteine biosynthesis pathways as major SL targets inVHL-inactivated cancer cells. Follow-up studies provided cellular and mechanistic insights into SL interactions of these pathway genes with theVHLgene.ConclusionsUsing isogenic CRISPR screening approach, we uncovered novel biological processes that are SL withVHL, which can be exploited for drug development for ccRCC. Our CRISPR and RNA-seq datasets provide a rich resource for future investigation of the function of the VHL tumor suppressor protein. Our work demonstrates the efficiency of CRISPR-based synthetic lethality screening in human isogenic cell pairs. Similar strategies could be employed to unveil SL partners with other oncogenic drivers.

scholarly journals A role for Arabidopsis growth-regulating factors 1 and 3 in growth–stress antagonism

2019 ◽  
Vol 71 (4) ◽  
pp. 1402-1417 ◽  
Author(s):  
Sarbottam Piya ◽  
Jinyi Liu ◽  
Tessa Burch-Smith ◽  
Thomas J Baum ◽  
Tarek Hewezi
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Growth Stress ◽  
Plant Responses ◽  
Chip Sequencing ◽  
Downstream Target ◽  
Genome Wide ◽  
Abiotic Stimuli ◽  
Regulatory Functions ◽  
Core Genes

Abstract Growth-regulating factors (GRFs) belong to a small family of transcription factors that are highly conserved in plants. GRFs regulate many developmental processes and plant responses to biotic and abiotic stimuli. Despite the importance of GRFs, a detailed mechanistic understanding of their regulatory functions is still lacking. In this study, we used ChIP sequencing (ChIP-seq) to identify genome-wide binding sites of Arabidopsis GRF1 and GRF3, and correspondingly their direct downstream target genes. RNA-sequencing (RNA-seq) analysis revealed that GRF1 and GRF3 regulate the expression of a significant number of the identified direct targets. The target genes unveiled broad regulatory functions of GRF1 and GRF3 in plant growth and development, phytohormone biosynthesis and signaling, and the cell cycle. Our analyses also revealed that clock core genes and genes with stress- and defense-related functions are most predominant among the GRF1- and GRF3-bound targets, providing insights into a possible role for these transcription factors in mediating growth–defense antagonism and integrating environmental stimuli into developmental programs. Additionally, GRF1 and GRF3 target molecular nodes of growth–defense antagonism and modulate the levels of defense- and development-related hormones in opposite directions. Taken together, our results point to GRF1 and GRF3 as potential key determinants of plant fitness under stress conditions.

scholarly journals Genome-wide strategies identify downstream target genes of chick connective tissue-associated transcription factors

Development ◽  
2018 ◽  
Vol 145 (7) ◽  
pp. dev161208 ◽  
Author(s):  
Mickael Orgeur ◽  
Marvin Martens ◽  
Georgeta Leonte ◽  
Sonya Nassari ◽  
Marie-Ange Bonnin ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Connective Tissue ◽  
Target Genes ◽  
Downstream Target ◽  
Genome Wide

scholarly journals Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2446
Author(s):  
Haim Werner ◽  
Rive Sarfstein ◽  
Karthik Nagaraj ◽  
Zvi Laron
Keyword(s):  
Growth Hormone Receptor ◽  
Target Genes ◽  
Relevant Information ◽  
Biological Properties ◽  
Laron Syndrome ◽  
Downstream Target ◽  
Barr Virus ◽  
Genome Wide ◽  
A Genome ◽  
Epstein Barr

Laron syndrome (LS) is a rare genetic endocrinopathy that results from mutation of the growth hormone receptor (GH-R) gene and is typically associated with dwarfism and obesity. LS is the best characterized entity under the spectrum of the congenital insulin-like growth factor-1 (IGF1) deficiencies. Epidemiological analyses have shown that LS patients do not develop cancer, whereas heterozygous family members have a cancer prevalence similar to the general population. To identify genes and signaling pathways differentially represented in LS that may help delineate a biochemical and molecular basis for cancer protection, we have recently conducted a genome-wide profiling of LS patients. Studies were based on our collection of Epstein–Barr virus (EBV)-immortalized lymphoblastoid cell lines derived from LS patients, relatives and healthy controls. Bioinformatic analyses identified differences in gene expression in several pathways, including apoptosis, metabolic control, cytokine biology, Jak-STAT and PI3K-AKT signaling, etc. Genes involved in the control of cell cycle, motility, growth and oncogenic transformation are, in general, down-regulated in LS. These genetic events seem to have a major impact on the biological properties of LS cells, including proliferation, apoptosis, response to oxidative stress, etc. Furthermore, genomic analyses allowed us to identify novel IGF1 downstream target genes that have not been previously linked to the IGF1 signaling pathway. In summary, by ‘mining’ genomic data from LS patients, we were able to generate clinically-relevant information in oncology and, potentially, related disciplines.

Sign in / Sign up

Export Citation Format

Share Document