Insulin Gene Expression Is Regulated by DNA Methylation

BACKGROUND:Insulin is a critical component of metabolic control, and as such, insulin gene expression has been the focus of extensive study. DNA sequences that regulate transcription of the insulin gene and the majority of regulatory factors have already been identified. However, only recently have other components of insulin gene expression been investigated, and in this study we examine the role of DNA methylation in the regulation of mouse and human insulin gene expression. METHODOLOGY/PRINCIPAL FINDINGS:Genomic DNA samples from several tissues were bisulfite-treated and sequenced which revealed that cytosine-guanosine dinucleotide (CpG) sites in both the mouse Ins2 and human INS promoters are uniquely demethylated in insulin-producing pancreatic beta cells. Methylation of these CpG sites suppressed insulin promoter-driven reporter gene activity by almost 90% and specific methylation of the CpG site in the cAMP responsive element (CRE) in the promoter alone suppressed insulin promoter activity by 50%. Methylation did not directly inhibit factor binding to the CRE in vitro, but inhibited ATF2 and CREB binding in vivo and conversely increased the binding of methyl CpG binding protein 2 (MeCP2). Examination of the Ins2 gene in mouse embryonic stem cell cultures revealed that it is fully methylated and becomes demethylated as the cells differentiate into insulin-expressing cells in vitro. CONCLUSIONS/SIGNIFICANCE:Our findings suggest that insulin promoter CpG demethylation may play a crucial role in beta cell maturation and tissue-specific insulin gene expression

Embarking on discovering resilient mechanisms: combining language use analysis with neuroscience.

Novel treatments in mental health focus on one’s ability to recover and develop resilience. Current concepts are based on The Adaptations Level Theory, which describes the ability of resilient individuals to accustom to new and even downgraded conditions as the new standard, find meaning in trauma, and adapt to new social settings. However, it is not known which treatments specifically help to build up resilience in patients and how to reliably screen for it. Recent studies demonstrated that distinct patterns of language use correlated with various mental health conditions. Utilizing text samples from the Holocaust survivors, we studied language use in resilient individuals compares to people with PTSD and general population. Holocaust survivors' language use was significantly different from PTSD sufferers, which suggests that we detected a possible resilience word use pattern. Next, we looked into the brain circuitry mechanisms that could be involved in resilience. We found that norepinephrine, the key neurotransmitter in stress response, modulated the activity of amygdala circuitry in a non-linear concentration-dependent manner. The shape and other characteristics of this dependency could be associated with the capacity for resilience

Embarking on discovering the mechanisms of resilience: combining language use analysis with neuroscience.

Novel treatments in mental health focus on one’s ability to recover and develop resilience. Current concepts are based on The Adaptations Level Theory, which describes the ability of resilient individuals to accustom to new and even downgraded conditions as the new standard, find meaning in trauma, and adapt to new social settings. However, it is not known which treatments specifically help to build up resilience in patients and how to reliably screen for it. Recent studies demonstrated that distinct patterns of language use correlated with various mental health conditions. Utilizing text samples from the Holocaust survivors, we studied language use in resilient individuals compares to people with PTSD and general population. Holocaust survivors' language use was significantly different from PTSD sufferers, which suggests that we detected a possible resilience word use pattern. Next, we looked into the brain circuitry mechanisms that could be involved in resilience. We found that norepinephrine, the key neurotransmitter in stress response, modulated the activity of amygdala circuitry in a non-linear concentration-dependent manner. The shape and other characteristics of this dependency could be associated with the capacity for resilience

Dysregulation of DNA methylation during development as a potential mechanisms contributing to obsessive compulsive disorders and autism

Autism Spectrum Disorder (ASD) is a pervasive developmental disorder, that is raising at a concerning rate. However, underlying mechanisms are still to be discovered. Obsessions and compulsions are the most debilitating aspect of these disorders (OCD), and they are the treatment priority for patients. SAPAP3 knock out mice present a reliable mouse model for repetitive compulsive behavior and are mechanistically closely related to the ASD mouse model Shank3 on a molecular level and AMPA receptor net effect. The phenotype of SAPAP3 knock out mice is obsessive grooming that leads to self-inflicted lesions by 4 months of age. Recent studies have accumulated evidence, that epigenetic mechanisms are important effectors in psychiatric conditions such as ASD and OCD. Methylation is the most studied mechanism, that recently lead to drug developments for more precise cancer treatments. We injected SAPAP3 mice with an epigenetic demethylation drug RG108 during pregnancy and delayed the onset of the phenotype in the offspring by 4 months. This result gives us clues about possible mechanism involved in OCD and ASD. Additionally, it shows that modulation of methylation mechanisms during development might be explored as a preventative treatment in the cases of high inherited risk of certain mental health conditions

Screening word usage in people affected by PTSD: an unbiased, cost effective, and novel screening method?

According to the World Health Organization, mental illness is the leading cause of disability worldwide accounting for 37% of years of healthy life lost. Prevention and early detection of mental health disorders is important for social stability and economic prosperity of every country and the world at large. Posttraumatic Stress Disorder (PTSD) is a very common condition with more than 3 million cases per year in the US alone. PTSD symptoms usually start soon after a traumatic event. The right diagnosis in a timely manner is key to ensuring prompt treatment that could lead to a full recovery. Unfortunately, social stigma as well as self-presentation and self-assessment biases often prevent individuals from seeking timely evaluation, leading to delays in treatment and suboptimal outcomes. Previous studies show that various mental health conditions are associated with distinct patterns of language use. Analyzing language use may also help to avoid response bias in self-reports. In this study we show a number of language use differences between PTSD sufferers and controls. Our data also suggest that subgroups of people with the same mental health disorder (PTSD in this study) may have salient differences in their language use, particularly in word usage frequencies. Additionally, we show that word usage patterns may vary depending on the type of the text being analyzed. These factors need to be accounted for when creating screening tools based on language analysis. If properly developed, such tools may facilitate earlier PTSD diagnosis, leading to timely support and treatment, which are associated with better outcomes

Measurements of the Total and Differential Higgs Boson Production Cross Sections Combining the H??????? and H???ZZ*???4??? Decay Channels at s\sqrt{s}=8??????TeV with the ATLAS Detector

Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3~fb$^{-1}$ of $pp$ collisions produced by the Large Hadron Collider at a center-of-mass energy of $\sqrt{s} = 8$ TeV and recorded by the ATLAS detector. Cross sections are obtained from measured $H \rightarrow \gamma \gamma$ and $H \rightarrow ZZ ^{*}\rightarrow 4\ell$ event yields, which are combined accounting for detector efficiencies, fiducial acceptances and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be $\sigma_{pp \to H} = 33.0 \pm 5.3 \, ({\rm stat}) \pm 1.6 \, ({\rm sys}) \mathrm{pb}$. The measurements are compared to state-of-the-art predictions.Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3  fb-1 of pp collisions produced by the Large Hadron Collider at a center-of-mass energy of s=8  TeV and recorded by the ATLAS detector. Cross sections are obtained from measured H→γγ and H→ZZ*→4ℓ event yields, which are combined accounting for detector efficiencies, fiducial acceptances, and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be σpp→H=33.0±5.3 (stat)±1.6 (syst)  pb. The measurements are compared to state-of-the-art predictions.Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3 fb$^{-1}$ of $pp$ collisions produced by the Large Hadron Collider at a center-of-mass energy of $\sqrt{s} = 8$ TeV and recorded by the ATLAS detector. Cross sections are obtained from measured $H \rightarrow \gamma \gamma$ and $H \rightarrow ZZ ^{*}\rightarrow 4\ell$ event yields, which are combined accounting for detector efficiencies, fiducial acceptances and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be $\sigma_{pp \to H} = 33.0 \pm 5.3 \, ({\rm stat}) \pm 1.6 \, ({\rm sys}) \mathrm{pb}$. The measurements are compared to state-of-the-art predictions