Upregulated Signaling Pathways in Ruptured Human Saccular Intracranial Aneurysm Wall: An Emerging Regulative Role of Toll-Like Receptor Signaling and Nuclear Factor-κB, Hypoxia-Inducible Factor-1A, and ETS Transcription Factors

Neurosurgery ◽  
2011 ◽  
Vol 68 (6) ◽  
pp. 1667-1676 ◽  
Author(s):  
Mitja I. Kurki ◽  
Sanna-Kaisa Häkkinen ◽  
Juhana Frösen ◽  
Riikka Tulamo ◽  
Mikael von und zu Fraunberg ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Intracranial Aneurysm ◽  
Signaling Pathways ◽  
Binding Sites ◽  
Hypoxia Inducible Factor ◽  
Transcription Factor Binding Sites ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Factor Binding

Abstract BACKGROUND: Aneurysmal subarachnoid hemorrhage, almost always from saccular intracranial aneurysm (sIA), is a devastating form of stroke that affects the working-age population. Cellular and molecular mechanisms predisposing to the rupture of the sIA wall are largely unknown. This knowledge would facilitate the design of novel diagnostic tools and therapies for the sIA disease. OBJECTIVE: To investigate gene expression patterns distinguishing ruptured and unruptured sIA. METHODS: We compared the whole-genome expression profile of 11 ruptured sIA wall samples with that of 8 unruptured ones using oligonucleotide microarrays. Signaling pathways enriched in the ruptured sIA walls were identified with bioinformatic analyses. Their transcriptional control was predicted in silico by seeking the enrichment of conserved transcription factor binding sites in the promoter regions of differentially expressed genes. RESULTS: Overall, 686 genes were significantly upregulated and 740 were downregulated in the ruptured sIA walls. Significantly upregulated biological processes included response to turbulent blood flow, chemotaxis, leukocyte migration, oxidative stress, vascular remodeling; and extracellular matrix degradation. Toll-like receptor signaling and nuclear factor-κB, hypoxia-inducible factor-1A, and ETS transcription factor binding sites were significantly enriched among the upregulated genes. CONCLUSION: We identified pathways and candidate genes associated with the rupture of human sIA wall. Our results may provide clues to the molecular mechanism in sIA wall rupture and insight for novel therapeutic strategies to prevent rupture.

scholarly journals Increased Induction of Osteopetrosis, but Unaltered Lymphomagenicity, by Murine Leukemia Virus SL3-3 after Mutation of a Nuclear Factor 1 Site in the Enhancer

1999 ◽  
Vol 73 (12) ◽  
pp. 10406-10415 ◽  
Author(s):  
Steen Ethelberg ◽  
Barbara D. Tzschaschel ◽  
Arne Luz ◽  
Salvador J. Diaz-Cano ◽  
Finn Skou Pedersen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Transcription Factor Binding Sites ◽  
Nuclear Factor ◽  
Wild Type ◽  
Factor Binding ◽  
Nuclear Factor 1 ◽  
Murine Leukemia

ABSTRACT SL3-3 is a murine leukemia virus which is only weakly bone pathogenic but highly T-cell lymphomagenic. A major pathogenic determinant is the transcriptional enhancer comprising several transcription factor binding sites, among which are three identical sites for nuclear factor 1 (NF1). We have investigated the pathogenic properties of NF1 site enhancer mutants of SL3-3. Two different mutants carrying a 3-bp mutation either in all three NF1 sites or in the central site alone were constructed and assayed in inbred NMRI mice. The wild type and both mutants induced lymphomas in all mice, with a mean latency period of 9 weeks. However, there was a considerable difference in osteopetrosis induction. Wild-type SL3-3 induced osteopetrosis in 11% of the mice (2 of 19), and the triple NF1 site mutant induced osteopetrosis in none of the mice (0 of 19), whereas the single NF1 site mutant induced osteopetrosis in 56% (10 of 18) of the mice, as determined by X-ray analysis. A detailed histological examination of the femurs of the mice was carried out and found to support this diagnosis. Thus, the NF1 sites of SL3-3 are major determinants of osteopetrosis induction, without determining lymphomagenesis. This conclusion was further supported by evaluation of the bone pathogenicity of other SL3-3 enhancer variants, the lymphomagenicity of which had been examined previously. This evaluation furthermore strongly indicated that the core sites, a second group of transcription factor binding sites in the viral enhancer, are necessary for the osteopetrosis induction potential of SL3-3.

scholarly journals Prediction of Transcription Factor Binding Sites of SP1 on Human Chromosome1

2021 ◽  
Vol 11 (11) ◽  
pp. 5123
Author(s):  
Maiada M. Mahmoud ◽  
Nahla A. Belal ◽  
Aliaa Youssif
Keyword(s):  
Transcription Factor ◽  
Binding Sites ◽  
Messenger Rna ◽  
Area Under The Curve ◽  
Noisy Data ◽  
Transcription Factor Binding Sites ◽  
Classification Problem ◽  
Transcription Factor Binding ◽  
K Nearest Neighbors ◽  
Factor Binding

Transcription factors (TFs) are proteins that control the transcription of a gene from DNA to messenger RNA (mRNA). TFs bind to a specific DNA sequence called a binding site. Transcription factor binding sites have not yet been completely identified, and this is considered to be a challenge that could be approached computationally. This challenge is considered to be a classification problem in machine learning. In this paper, the prediction of transcription factor binding sites of SP1 on human chromosome1 is presented using different classification techniques, and a model using voting is proposed. The highest Area Under the Curve (AUC) achieved is 0.97 using K-Nearest Neighbors (KNN), and 0.95 using the proposed voting technique. However, the proposed voting technique is more efficient with noisy data. This study highlights the applicability of the voting technique for the prediction of binding sites, and highlights the outperformance of KNN on this type of data. The study also highlights the significance of using voting.

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