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Hussein S.M.I.,Lunenfeld Tanenbaum Research Institute | Puri M.C.,Lunenfeld Tanenbaum Research Institute | Puri M.C.,University of Toronto | Tonge P.D.,Lunenfeld Tanenbaum Research Institute | And 45 more authors.
Nature | Year: 2014

Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic, epigenomic and proteomic data sets describing the reprogramming routes leading from mouse embryonic fibroblasts to induced pluripotency. Through integrative analysis, we reveal that cells transition through distinct gene expression and epigenetic signatures and bifurcate towards reprogramming transgene-dependent and-independent stable pluripotent states. Early transcriptional events, driven by high levels of reprogramming transcription factor expression, are associated with widespread loss of histone H3 lysine 27 (H3K27me3) trimethylation, representing a general opening of the chromatin state. Maintenance of high transgene levels leads to re-acquisition of H3K27me3 and a stable pluripotent state that is alternative to the embryonic stem cell (ESC)-like fate. Lowering transgene levels at an intermediate phase, however, guides the process to the acquisition of ESC-like chromatin and DNA methylation signature. Our data provide a comprehensive molecular description of the reprogramming routes and is accessible through the Project Grandiose portal at http://www.stemformatics.org. © 2014 Macmillan Publishers Limited. Source

Lindam A.,Karolinska Institutet | Lindam A.,QIMRBerghofer Medical Research Institute | Kendall B.J.,QIMRBerghofer Medical Research Institute | Kendall B.J.,University of Queensland | And 6 more authors.
PLoS ONE | Year: 2015

Background: Gastroesophageal reflux is overrepresented in people with obstructive sleep apnea (OSA) and it has been suggested that OSA worsens gastroesophageal reflux symptoms. Aggravated reflux might lead to an increased risk of Barrett's esophagus. Aim: To assess the association between sleep apnea symptoms and Barrett's esophagus. Methods: Included in a case-control study in Brisbane, Australia were 237 patients with histologically confirmed Barrett's esophagus and 247 population controls. The controls were randomly selected from the electoral roll and frequency-matched to the cases by age and sex. Information on OSA symptoms (excessive daytime sleepiness and sleep related apnea symptoms), gastroesophageal reflux symptoms and anthropometric measures were collected through interviews and written questionnaires. Multivariable logistic regression provided odds ratios (OR) and 95% confidence intervals (CI), adjusted for potential confounding by BMI and gastroesophageal reflux. Results: The prevalence of Barrett's esophagus was higher among people with excessive daytime sleepiness than those without (24% vs. 18%; p-value 0.1142) and in participants with sleeprelated apnea symptoms (20% vs. 13%; p-value 0.1730). However, there were non-significantly increased ORs of Barrett's esophagus among people with excessive daytime sleepiness (OR 1.42, 95% CI 0.90-2.34) and sleep related apnea symptoms (OR 1.32, 95% CI 0.74-2.36) when adjusting for age, sex and BMI. After further adjustment for gastroesophageal reflux symptoms, the point ORs were no longer increased (OR 1.02, 95% CI 0.61-1.70 for daytime sleepiness and OR 0.72, 95% CI 0.38-1.38 for sleep related apnea symptoms). Conclusions: Symptoms of OSA are possibly associated with an increased risk of Barrett's esophagus, an association that appears to be mediated entirely by gastroesophageal reflux. Copyright: © 2015 Lindam et al. Source

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