RESUMO
BACKGROUND: Common diseases manifest differentially between patients, but the genetic origin of this variation remains unclear. To explore possible involvement of gene transcriptional-variation, we produce a DNA methylation-oriented, driver-gene-wide dataset of regulatory elements in human glioblastomas and study their effect on inter-patient gene expression variation. RESULTS: In 175 of 177 analyzed gene regulatory domains, transcriptional enhancers and silencers are intermixed. Under experimental conditions, DNA methylation induces enhancers to alter their enhancing effects or convert into silencers, while silencers are affected inversely. High-resolution mapping of the association between DNA methylation and gene expression in intact genomes reveals methylation-related regulatory units (average size = 915.1 base-pairs). Upon increased methylation of these units, their target-genes either increased or decreased in expression. Gene-enhancing and silencing units constitute cis-regulatory networks of genes. Mathematical modeling of the networks highlights indicative methylation sites, which signified the effect of key regulatory units, and add up to make the overall transcriptional effect of the network. Methylation variation in these sites effectively describe inter-patient expression variation and, compared with DNA sequence-alterations, appears as a major contributor of gene-expression variation among glioblastoma patients. CONCLUSIONS: We describe complex cis-regulatory networks, which determine gene expression by summing the effects of positive and negative transcriptional inputs. In these networks, DNA methylation induces both enhancing and silencing effects, depending on the context. The revealed mechanism sheds light on the regulatory role of DNA methylation, explains inter-individual gene-expression variation, and opens the way for monitoring the driving forces behind deferential courses of cancer and other diseases.
Assuntos
Metilação de DNA , Sequências Reguladoras de Ácido Nucleico , Humanos , Regulação da Expressão Gênica , MutaçãoRESUMO
BACKGROUND: Malaria infection during pregnancy is a major public health problem. Due to increasing resistance to Chloroquine and Sulphadoxine/Pyrimethamine, the Ugandan national policy on malaria treatment was changed in 2005 to Artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria. The policy recommends assessment of safety and efficacy of alternative drugs for treatment of uncomplicated malaria. We compared the efficacy and safety of Artemether-Lumefantrine (Coartem) and Chlorproguanil-Dapsone (Lapdap) in the management of uncomplicated malaria in pregnancy. METHODOLOGY: We enrolled 110 pregnant women in the second and third trimester of pregnancy who presented to Mulago hospital, Uganda, with uncomplicated malaria. The study design was an open-label randomized clinical trial. Participants were randomized to receive either Artemether-Lumefantrine (Coartem 20 mg/120 mg) orally or Chlorproguanil-Dapsone (Lapdap) orally for 3 consecutive days. Primary endpoints were clinical and parasitological response assessed on days 0, 1, 2, 4, 7, 14 and 28. Adverse effects, clinical response (treatment failure) and parasitological response were compared. Analysis was by intention to treat. RESULTS: Of the 100 women who completed the study, there was no statistically significant difference in clinical and parasitological response by Day 4. The mean fever clearance time 3.0 days with Lapdap versus 2.5 days with Coartem was comparable. Likewise, mean parasite clearance time of 2.4 and 2.2 days for Lapdap and Coartem respectively was comparable. The adverse effects were comparable between the two groups. CONCLUSION: Artemether-Lumefantrine and Chlorproguanil-Dapsone have high and comparable cure rates and similar safety profiles when used for treatment of uncomplicated malaria in pregnancy.