Fine Tuning of Globin Gene Expression by DNA Methylation

Expression patterns in the globin gene cluster are subject to developmental regulation in vivo. While the γ(A) and γ(G) genes are expressed in fetal liver, both are silenced in adult erythrocytes. In order to decipher the role of DNA methylation in this process, we generated a YAC transgenic mouse system that allowed us to control γ(A) methylation during development. DNA methylation causes a 20-fold repression of γ(A) both in non-erythroid and adult erythroid cells. In erythroid cells this modification works as a dominant mechanism to repress γ gene expression, probably through changes in histone acetylation that prevent the binding of erythroid transcription factors to the promoter. These studies demonstrate that DNA methylation serves as an elegant in vivo fine-tuning device for selecting appropriate genes in the globin locus. In addition, our findings provide a mechanism for understanding the high levels of γ-globin transcription seen in patients with Hereditary Persistence of Fetal Hemoglobin, and help explain why 5azaC and butyrate compounds stimulate γ-globin expression in patients with β-hemoglobinopathies

Role of Basal Ganglia Circuits in Resisting Interference by Distracters: A swLORETA Study

BACKGROUND: The selection of task-relevant information requires both the focalization of attention on the task and resistance to interference from irrelevant stimuli. Both mechanisms rely on a dorsal frontoparietal network, while focalization additionally involves a ventral frontoparietal network. The role of subcortical structures in attention is less clear, despite the fact that the striatum interacts significantly with the frontal cortex via frontostriatal loops. One means of investigating the basal ganglia's contributions to attention is to examine the features of P300 components (i.e. amplitude, latency, and generators) in patients with basal ganglia damage (such as in Parkinson's disease (PD), in which attention is often impaired). Three-stimulus oddball paradigms can be used to study distracter-elicited and target-elicited P300 subcomponents. METHODOLOGY/PRINCIPAL FINDINGS: In order to compare distracter- and target-elicited P300 components, high-density (128-channel) electroencephalograms were recorded during a three-stimulus visual oddball paradigm in 15 patients with early PD and 15 matched healthy controls. For each subject, the P300 sources were localized using standardized weighted low-resolution electromagnetic tomography (swLORETA). Comparative analyses (one-sample and two-sample t-tests) were performed using SPM5® software. The swLORETA analyses showed that PD patients displayed fewer dorsolateral prefrontal (DLPF) distracter-P300 generators but no significant differences in target-elicited P300 sources; this suggests dysfunction of the DLPF cortex when the executive frontostriatal loop is disrupted by basal ganglia damage. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the cortical attention frontoparietal networks (mainly the dorsal one) are modulated by the basal ganglia. Disruption of this network in PD impairs resistance to distracters, which results in attention disorders

Fetal haemoglobin levels in adult type 1 (insulin-dependent) diabetic patients

Glycated haemoglobin levels (HbA1 and HbA1c) are established parameters of long-term glycaemic control in diabetic patients. Depending on the method used, fetal haemoglobin interferes with the assays for glycated haemoglobin. If present in high amounts, fetal haemoglobin may lead to overestimation of glycated haemoglobin levels, and therefore, of average blood glucose concentration in diabetic patients. Glycated (HbA1c) and fetal haemoglobin levels were measured by high pressure liquid chromatography in 60 (30 female) adult Type 1 (insulin-dependent) diabetic patients of Swiss descent, and were compared with levels obtained from 60 normal, non-diabetic control subjects matched for age and sex. Fetal haemoglobin levels were significantly higher in the diabetic patients (0.6 +/- 0.1%, mean +/- SEM; range: 0-3.6%) than in the control subjects (0.4 +/- 0.1%, p or = 0.6%) were found in 23 of 60 diabetic patients (38%) compared to 9 of 60 control subjects (15%; chi 2 = 8.35, p < 0.01). In addition, fetal haemoglobin levels in diabetic patients are weakly correlated with glycated haemoglobin (HbA1c) (r = 0.38, p < 0.01). Fetal haemoglobin results were confirmed with the alkali denaturation procedure, and by immunocytochemistry using a polyclonal rabbit anti-fetal haemoglobin antibody. A significant proportion of adult patients with Type 1 diabetes has elevated fetal haemoglobin levels. In certain patients this may lead to a substantial over-estimation of glycated haemoglobin levels, and consequently of estimated, average blood glucose levels. The reason for this increased prevalence of elevated fetal haemoglobin remains unclear, but it may be associated with poor glycaemic control