scholarly journals LncRNAOIP5-AS1is overexpressed in undifferentiated oral tumors and integrated analysis identifies as a downstream effector of stemness-associated transcription factors

2018 ◽  
Author(s):  
Ganesan Arunkumar ◽  
Shankar Anand ◽  
Partha Raksha ◽  
Shankar Dhamodharan ◽  
Harikrishnan Prasanna Srinivasa Rao ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Binding Site ◽  
Target Genes ◽  
Integrated Analysis ◽  
Downstream Target ◽  
Cellular Processes ◽  
Downstream Effector ◽  
Undifferentiated Tumors ◽  
Oral Tumors ◽  
High Level

AbstractLong non-coding RNAs (lncRNAs) play an important role in the regulation of key cellular processes in early development and in cancer. LncRNAOip5-as1facilitates stem cell self-renewal in mouse by sponging mmu-miR-7 and modulating NANOG level, yet its role in cancer is less understood. We analyzedOIP5-AS1expression in oral tumors and in TCGA datasets. We observed overexpression ofOIP5-AS1in oral tumors (P<0.001) and in tumors of epithelial origin from TCGA.OIP5-AS1expression was strongly associated with undifferentiated tumors (P=0.0038).In silicoanalysis showed miR-7 binding site is conserved in mouse and humanOIP5-AS1. However, humanNANOG3’-UTR lost the binding site for hsa-miR-7a-3. Therefore, we screened for other miRNAs that can be sponged byOIP5-AS1and identified six potential miRNAs and their downstream target genes. Expression analysis showed downregulation of miRNAs and upregulation of downstream target genes, particularly in undifferentiated tumors with high-level ofOIP5-AS1suggesting thatOIP5-AS1could post-transcriptionally modulate the downstream target genes. Further, systematic epigenomic analysis ofOIP5-AS1promoter revealed binding motifs for MYC, NANOG and KLF4 suggesting thatOIP5-AS1could be transactivated by stemness-associated transcription factors in cancer. Overexpression of OIP5-AS1 in undifferentiated oral tumors may confer poor prognosis through maintenance of cancer stemness.

scholarly journals LncRNA OIP5-AS1 is overexpressed in undifferentiated oral tumors and integrated analysis identifies as a downstream effector of stemness-associated transcription factors

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Ganesan Arunkumar ◽  
Shankar Anand ◽  
Partha Raksha ◽  
Shankar Dhamodharan ◽  
Harikrishnan Prasanna Srinivasa Rao ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Integrated Analysis ◽  
Downstream Effector ◽  
Oral Tumors

scholarly journals Screening Driving Transcription Factors in the Processing of Gastric Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Guangzhong Xu ◽  
Kai Li ◽  
Nengwei Zhang ◽  
Bin Zhu ◽  
Guosheng Feng
Keyword(s):  
Gastric Cancer ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Expression Profiles ◽  
Functional Enrichment ◽  
Regulatory Mechanisms ◽  
Integrated Analysis ◽  
Transcriptional Regulatory

Background. Construction of the transcriptional regulatory network can provide additional clues on the regulatory mechanisms and therapeutic applications in gastric cancer.Methods. Gene expression profiles of gastric cancer were downloaded from GEO database for integrated analysis. All of DEGs were analyzed by GO enrichment and KEGG pathway enrichment. Transcription factors were further identified and then a global transcriptional regulatory network was constructed.Results. By integrated analysis of the six eligible datasets (340 cases and 43 controls), a bunch of 2327 DEGs were identified, including 2100 upregulated and 227 downregulated DEGs. Functional enrichment analysis of DEGs showed that digestion was a significantly enriched GO term for biological process. Moreover, there were two important enriched KEGG pathways: cell cycle and homologous recombination. Furthermore, a total of 70 differentially expressed TFs were identified and the transcriptional regulatory network was constructed, which consisted of 566 TF-target interactions. The top ten TFs regulating most downstream target genes were BRCA1, ARID3A, EHF, SOX10, ZNF263, FOXL1, FEV, GATA3, FOXC1, and FOXD1. Most of them were involved in the carcinogenesis of gastric cancer.Conclusion. The transcriptional regulatory network can help researchers to further clarify the underlying regulatory mechanisms of gastric cancer tumorigenesis.

scholarly journals Cell transformation mediated by homodimeric E2A-HLF transcription factors.

1997 ◽  
Vol 17 (3) ◽  
pp. 1417-1424 ◽  
Author(s):  
T Inukai ◽  
T Inaba ◽  
T Yoshihara ◽  
A T Look
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Fusion Gene ◽  
Dominant Negative ◽  
Fusion Product ◽  
3T3 Cells ◽  
Par Proteins ◽  
Downstream Target ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

The E2A-HLF fusion gene, created by the t(17;19)(q22;p13) chromosomal translocation in pro-B lymphocytes, encodes an oncogenic protein in which the E2A trans-activation domain is linked to the DNA-binding and protein dimerization domain of hepatic leukemia factor (HLF), a member of the proline- and acidic amino acid-rich (PAR) subfamily of bZIP transcription factors. This fusion product binds to its DNA recognition site not only as a homodimer but also as a heterodimer with HLF and two other members of the PAR bZIP subfamily, thyrotroph embryonic factor (TEF) and albumin promoter D-box binding protein (DBP). Thus, E2A-HLF could transform cells by direct regulation of downstream target genes, acting through homodimeric or heterodimeric complexes, or by sequestering normal PAR proteins into nonfunctional heterocomplexes (dominant-negative interference). To distinguish among these models, we constructed mutant E2A-HLF proteins in which the leucine zipper domain of HLF was extended by one helical turn or altered in critical charged amino acids, enabling the chimera to bind to DNA as a homodimer but not as a heterodimer with HLF or other PAR proteins. When introduced into NIH 3T3 cells in a zinc-inducible vector, each of these mutants induced anchorage-independent growth as efficiently as unaltered E2A-HLF, indicating that the chimeric oncoprotein can transform cells in its homodimeric form. Transformation also depended on an intact E2A activator region, providing further support for a gain-of-function contribution to oncogenesis rather than one based on a dominant-interfering or dominant-negative mechanism. Thus, the tumorigenic effects of E2A-HLF and its mutant forms in NIH 3T3 cells favor a straightforward model in which E2A-HLF homodimers bind directly to promoter/enhancer elements of downstream target genes and alter their patterns of expression in early B-cell progenitors.

scholarly journals Potential Downstream Target Genes of Aberrant ETS Transcription Factors Are Differentially Affected in Ewing’s Sarcoma and Prostate Carcinoma

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49819 ◽  
Author(s):  
Maria J. Camões ◽  
Paula Paulo ◽  
Franclim R. Ribeiro ◽  
João D. Barros-Silva ◽  
Mafalda Almeida ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Prostate Carcinoma ◽  
Target Genes ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Ets Transcription Factors ◽  
Downstream Target

Regulation and function of homeodomain proteins in the embryonic and adult vascular systemsThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.

2007 ◽  
Vol 85 (1) ◽  
pp. 55-65 ◽  
Author(s):  
Josette M. Douville ◽  
Jeffrey T. Wigle
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Vascular System ◽  
Homeobox Genes ◽  
Tube Formation ◽  
Binding Motif ◽  
Homeodomain Proteins ◽  
Downstream Target ◽  
Endothelial Tube Formation ◽  
And Function

During embryonic development, the cardiovascular system first forms and then gives rise to the lymphatic vascular system. Homeobox genes are essential for both the development of the blood and lymphatic vascular systems, as well as for their maintenance in the adult. These genes all encode proteins that are transcription factors that contain a well conserved DNA binding motif, the homeodomain. It is through the homeodomain that these transcription factors bind to the promoters of target genes and regulate their expression. Although many homeodomain proteins have been found to be expressed within the vascular systems, little is known about their downstream target genes. This review highlights recent advances made in the identification of novel genes downstream of the homeodomain proteins that are necessary for regulating vascular cellular processes such as proliferation, migration, and endothelial tube formation. Factors known to regulate the functions of vascular cells via modulating the expression of homeobox genes will be discussed. We will also review current methods used to identify and characterize downstream target genes of homeodomain proteins.

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 Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor

2020 ◽  
Vol 295 (52) ◽  
pp. 18284-18300
Author(s):  
Wei Shao ◽  
Jiwon Hwang ◽  
Chune Liu ◽  
Debaditya Mukhopadhyay ◽  
Shan Zhao ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Transcription Factors ◽  
Target Genes ◽  
Cultured Cells ◽  
Cell Metabolism ◽  
Control Cell ◽  
Hypoxia Inducible Factor ◽  
Mitochondrial Respiratory Chain ◽  
Serum Lipoprotein ◽  
Downstream Target

Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen.

scholarly journals Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders

2019 ◽  
Vol 28 (24) ◽  
pp. 4089-4102 ◽  
Author(s):  
Loredana Poeta ◽  
Agnese Padula ◽  
Benedetta Attianese ◽  
Mariaelena Valentino ◽  
Lucia Verrillo ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Neurodevelopmental Disorders ◽  
Target Genes ◽  
Downstream Target ◽  
Deacetylase Inhibitor ◽  
Core Feature ◽  
Genes Encoding ◽  
Vitro Analysis ◽  
In Vitro Analysis

Abstract A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in ARX/alr-1-deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.

scholarly journals Use of Differentiating Adult Stem Cells (Marrow Stromal Cells) to Identify New Downstream Target Genes for Transcription Factors

Stem Cells ◽  
2006 ◽  
Vol 24 (3) ◽  
pp. 642-652 ◽  
Author(s):  
Joni Ylöstalo ◽  
Jason R. Smith ◽  
Radhika R. Pochampally ◽  
Robert Matz ◽  
Ichiro Sekiya ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Stromal Cells ◽  
Adult Stem Cells ◽  
Target Genes ◽  
Marrow Stromal Cells ◽  
Downstream Target

scholarly journals An Overview of the Importance of Conformational Flexibility in Gene Regulation by the Transcription Factors

2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
Shagufta H. Khan ◽  
Raj Kumar
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Target Genes ◽  
Conformational Flexibility ◽  
Structural Basis ◽  
Biological Functions ◽  
Multiprotein Complexes ◽  
Cellular Processes ◽  
Intrinsically Disordered ◽  
Coregulatory Proteins

A number of proteins with intrinsically disordered (ID) regions/domains are reported to be found disproportionately higher in transcription factors. Available evidences suggest that presence of ID region/domain within a transcription factor plays an important role in its biological functions. These ID sequences provide large flexible surfaces that can allow them to make more efficient physical and functional interactions with their target partners. Since transcription factors regulate expression of target genes by interacting with specific coregulatory proteins, these ID regions/domains can be used as a platform for such large macromolecular interactions, and may represent a mechanism for regulation of cellular processes. The precise structural basis for the function of these ID regions/domains of the transcription factors remains to be determined. In the recent years there has been growing evidence suggesting that an induced fit-like process leads to imposition of folded functional structure in these ID domains on which large multiprotein complexes are built. These multiprotein complexes may eventually dictate the final outcome of the gene regulation by the transcription factors.

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