Biology subjects

Binder, E.

Publications and source records attributed to Binder, E..

10 recordsLinked to original sources

bioRxiv2024

A novel epigenetic clock for rhesus macaques unveils an association between early life adversity and epigenetic age acceleration

Because DNA methylation changes reliably with age, machine learning models called epigenetic clocks can estimate an individuals age based on their DNA methylation profile. This epigenetic measure of age can deviate from ones true age, and the difference between the epigenetic age and true age, known as epigenetic age acceleration (EAA), has been found to directly correlate with morbidity and mortality in adults. Emerging evidence suggests that EAA is also associated with aberrant health outcomes in children, making epigenetic clocks useful tools for studying aging and development. We developed two highly accurate epigenetic clocks for the rhesus macaque, utilizing 1,008 blood samples from 690 macaques between 2 days and 23.4 years of age with diverse genetic backgrounds and exposure to environmental conditions. The first clock, which is trained on all samples, achieves a Pearson correlation between true age and predicted age of 0.983 and median absolute error of 0.210 years. To study phenotypes during development, the second clock is optimized for macaques younger than 6 years and achieves a Pearson correlation of 0.974 and a median absolute error of 0.148 years. Using the latter clock, we investigated whether epigenetic aging is affected by early life adversity in the form of infant maltreatment. Our data suggests that maltreatment and increased hair cortisol levels are associated with epigenetic age acceleration right after the period of maltreatment.

neuroscience↗

bioRxiv2024

Differential Dynamics and Roles of FKBP51 Isoforms and Their Implications for Targeted Therapies

The expression of FKBP5, and its resulting protein FKBP51, is strongly induced by stress and glucocorticoids. Numerous studies have explored their involvement in a plethora of cellular processes and diseases, including psychiatric disorders, inflammatory conditions and cancer. However, there is a lack of knowledge on the role of the different RNA splicing variants and the two protein isoforms that originate from the human FKBP5 locus, especially in response to glucocorticoids. In this study we use in vitro models as well as peripheral blood cells of a human cohort to show that the two expressed variants are both dynamically upregulated following dexamethasone. We also investigate the subcellular localization of the protein isoforms, their degradation dynamics as well as their differential role in known cellular pathways. The results shed light on the difference of the two variants and highlight the importance of differential analyses in future studies with implications for targeted drug design.

molecular biology↗

bioRxiv2024

Polygenic risk for schizophrenia converges on alternative polyadenylation as molecular mechanism underlying synaptic impairment

Schizophrenia (SCZ) is a genetically heterogenous psychiatric disorder of highly polygenic nature. Correlative evidence from genetic studies indicate that the aggregated effects of distinct genetic risk factor combinations found in each patient converge onto common molecular mechanisms. To prove this on a functional level, we employed a reductionistic cellular model system for polygenic risk by differentiating induced pluripotent stem cells (iPSCs) from 104 individuals with high polygenic risk load and controls into cortical glutamatergic neurons (iNs). Multi-omics profiling identified widespread differences in alternative polyadenylation (APA) in the 3 untranslated region of many synaptic transcripts between iNs from SCZ patients and healthy donors. On the cellular level, 3APA was associated with a reduction in synaptic density of iNs. Importantly, differential APA was largely conserved between postmortem human prefrontal cortex from SCZ patients and healthy donors, and strongly enriched for transcripts related to synapse biology. 3APA was highly correlated with SCZ polygenic risk and affected genes were significantly enriched for SCZ associated common genetic variation. Integrative functional genomic analysis identified the RNA binding protein and SCZ GWAS risk gene PTBP2 as a critical trans-acting factor mediating 3APA of synaptic genes in SCZ subjects. Functional characterization of PTBP2 in iNs confirmed its key role in 3APA of synaptic transcripts and regulation of synapse density. Jointly, our findings show that the aggregated effects of polygenic risk converge on 3APA as one common molecular mechanism that underlies synaptic impairments in SCZ.

neuroscience↗

bioRxiv2021

Genotype and age influence cortical-FKBP5 at multiple regulatory and single-cell-type levels in severe psychiatric disorders

Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell-types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n=1024) of FKBP5/1 examining prefrontal cortex (BA9, BA11, BA24) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease-state, aging and genotype on cortical FKBP5/1 expression including in a cell-type specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq) and targeted histology, we established that these disease- and aging-effects on FKBP5/1 expression were most pronounced in excitatory supragranular neurons. We then found that this increase in FKBP5 levels likely impacts on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in supragranular neurons. These findings pinpoint a novel cellular and molecular mechanism that has significant potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.

neuroscience↗

bioRxiv2020

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2x10-7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

genetics↗

bioRxiv2020

POMC neurons functional heterogeneity relies on mTORC1 signaling

Hypothalamic Pro-opiomelanocortin (POMC) neurons are classically known to trigger satiety. However, they encompass heterogeneous subpopulations whose functions are unknown. Here we show that POMC neurons releasing GABA, glutamate or both neurotransmitters possess distinct spatial distribution, molecular signatures and functions. Functional specificity of these subpopulations relies on the energy sensor mechanistic Target of Rapamycin Complex 1 (mTORC1), since pharmacological blockade of mTORC1, by mimicking a cellular negative energy state, simultaneously inhibited POMC/glutamatergic and activated POMC/GABAergic neurons. Chemogenetics and conditional deletion of mTORC1 then demonstrated that mTORC1 blockade in POMC neurons causes hyperphagia. This is due to decreased POMC-derived anorexigenic -melanocyte-stimulating hormone and the recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Genetic inhibition of glutamate release from POMC neurons also produced hyperphagia, recapitulating the phenotype caused by mTORC1 blockade. Altogether, these findings pinpoint the molecular mechanisms engaged by POMC neurons to oppositely control feeding, thereby challenging conventional views about their functions.

neuroscience↗

bioRxiv2020

Cell-type specific impact of glucocorticoid receptor activation on the developing brain

A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing health outcomes. Excess GR-activation in utero has been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type specific effects. To address this, we used an in vitro model of fetal human brain, induced pluripotent-stem-cell-derived cerebral organoids, and mapped GR-activation effects using single-cell transcriptomics across development. Interestingly, neurons showed targeted regulation of differentiation- and maturation-related transcripts, suggesting a delay of these processes upon GR-activation. Uniquely in neurons, differentially-expressed transcripts were significantly enriched for genes associated with behavior-related phenotypes and disorders. This suggests that aberrant GR-activation could impact proper neuronal maturation, leading to increased disease susceptibility, through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure.

neuroscience↗

bioRxiv2019

Association between DNA methylation and ADHD symptoms from birth to school age: A prospective meta-analysis

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is not known. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school-age. We examined associations of DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age range 4-15 years) in 2477 children from five cohorts and DNA methylation at school-age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from ten cohorts. CpGs identified with nominal significance (p<0.05) in either of the EWAS were correlated between timepoints ({rho}=0.30), suggesting overlap in associations, however, top signals were very different. At birth, we identified nine CpGs that were associated with later ADHD symptoms (P<1*10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 located in the promotor region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which was associated with neurite outgrowth and an ADHD diagnosis in previous studies. In contrast, at school-age, no CpGs were associated with ADHD with P<1*10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

genetics↗

bioRxiv2018

Copy number variation in small nucleolar RNAs regulates personality behavior

The Prader-Willi Syndrome (PWS) gene region is an imprinted gene complex involved in behavioral, metabolic and osteogenic functions. We have analyzed here the variation of two families of regulatory small nucleolar RNAs (SNORD115 and SNORD116) that are coded within the PWS and are expressed from the paternal chromosome. They are organized in two tandemly repeated clusters which are naturally copy number variable between individuals. We find that the copy numbers at these loci correlate with repeatable individual test scores for anxiety that are considered to constitute a component of the "personality" of individuals. We show this for different populations and species of mice, cavies and for the anxiety component of personality tests in humans. This is also the case for an inbred mouse strain (C57Bl6) implying that copy number variation creates phenotypic variability even in an isogenic background. In transcriptome data from brain samples of this strain we find SNORD copy-number correlated regulation of target genes that are known to be involved in influencing behavior. SNORD115 has previously been suggested to regulate splicing of the serotonin receptor Htr2c and we confirm this in our data. For SNORD116 we provide evidence that it regulates the expression level of the chromatin regulator Ankrd11, which itself regulates GABA receptors, metabolic pathways, cell differentiation and osteogenesis. Intriguingly, we find that craniofacial shapes in mice correlate also with SNORD116 copy numbers. New copy number variants are generated at very high rates in mice, possibly at every generation, explaining why conventional genetic mapping could not detect this association. Our results suggest that the variable dosage of two regulatory RNAs are major determinants of individual behavioral differences and correlated traits in mammals.

evolutionary biology↗

bioRxiv2017

PTSD Blood Transcriptome Mega-Analysis: Shared Inflammatory Pathways Across Genders And Modes Of Traumas

Transcriptome-wide screens of peripheral blood during the onset and development of posttraumatic stress disorder (PTSD) indicate widespread immune dysregulation. However, little is known as to whether biological sex and the type of traumatic event influence shared or distinct biological pathways in PTSD. We performed a combined analysis of five independent PTSD blood transcriptome studies covering seven types of trauma in 229 PTSD and 311 comparison individuals to synthesize the extant data. Analyses by trauma type revealed a clear pattern of PTSD gene expression signatures distinguishing interpersonal (IP)-related traumas from combat-related traumas. Co-expression network analyses integrated all data and identified distinct gene expression perturbations across sex and modes of trauma in PTSD, including one wound-healing module down-regulated in men exposed to combat traumas, one IL12-mediated signaling module up-regulated in men exposed to IP-related traumas, and two modules associated with lipid metabolism and MAPK-activity up-regulated in women exposed to IP-related traumas. Remarkably, a high degree of sharing of transcriptional dysregulation across sex and modes of trauma in PTSD was also observed converging on common signaling cascades, including cytokine, innate immune and type I interferon pathways. Collectively, these findings provide a broad view of immune dysregulation in PTSD and demonstrate inflammatory pathways of molecular convergence and specificity, which may inform mechanisms and diagnostic biomarkers for the disorder.

neuroscience↗