Biology subjects

Zillich, L.

Publications and source records attributed to Zillich, L..

5 recordsLinked to original sources

bioRxiv2025

Dynamic Epigenetic Changes During Antidepressant Pharmacotherapy in Major Depressive Disorder

Although antidepressants remain the main pharmacological treatment for major depressive disorder (MDD), therapeutic response varies, highlighting the need for molecular markers that predict treatment response, as well as insights into the biological processes underlying antidepressant efficacy. Candidate-gene and cross-sectional epigenome-wide association studies (EWAS) have reported DNA methylation signatures associated with antidepressant response; however, findings remain inconsistent. To date, no longitudinal EWAS has examined methylation trajectories across multiple time points during antidepressant treatment in MDD. Within the Early Medication Change trial, DNA methylation data was generated for 162 patients with MDD (81 responders, 81 non-responders) and 48 matched healthy controls. Patients were assessed at four times across eight-weeks of standardized antidepressant treatment, while controls were assessed twice. Differentially methylated positions (DMPs) and regions (DMRs) were identified using longitudinal EWAS models and the comb-p algorithm. Baseline methylation levels were associated with depressive symptom severity at day 28 and day 56 through two and six DMRs, respectively (e.g., TNRC6C, CAT), whereas no single DMP reached significance. Longitudinal analyses identified one DMP associated with improvement in depressive symptoms (YLMP1) and three DMRs showing methylation changes over time (e.g., GPR126, PM20D1). Combined patient-control analyses revealed additional DMPs and DMRs associated with diagnosis and temporal effects. This study provides first longitudinal evidence of regionally coordinated DNA methylation changes during antidepressant pharmacotherapy, revealing alterations in genes involved in neuroplasticity and inflammatory processes that are associated with clinical response. Replication and functional validation will be essential to determine their relevance for personalized antidepressant treatment.

genomics↗

bioRxiv2025

Epigenome-wide Association Study of Psilocybin-Induced Methylome Changes in Alcohol Use Disorder

The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis of psilocybin-induced changes in a cohort of detoxified patients with AUD. The longitudinal study design included three assessment days in 40 patients with blood sampling and acquisition of psychometrics - at baseline, 24 hours after administration of psilocybin (25 mg) or placebo (mannitol), and one month after treatment. Our epigenome-wide association study (EWAS) identified one CpG site in TLE4 (p = 1.1e-7) associated with psilocybin treatment. Screening for differentially methylated regions, we observed altered methylation in the gene RASGRP4 (pFDR = 3.2e-4). Network analysis revealed co-methylation modules related to psilocybin treatment, as well as modules associated with the reduction of depressive symptoms and drinking behavior. Gene ontology analysis indicated involvement of these modules in neuroplasticity and immune functions, suggesting that they may reflect abstinence-related recovery processes. Investigating candidate genes at nominal significance (p < 0.05) uncovered promoter-associated methylation changes in HTR2A and TNF. Furthermore, at p < 0.05, we found baseline differences between treatment responders (< 1 standard unit alcohol in 4-week follow-up) and non-responders in genes related to synaptic plasticity and different neurotransmitter systems. While these findings are limited by the modest sample size, they align well with previous literature and might provide starting points for further, large-scale investigations or hypothesis-driven experiments.

pharmacology and toxicology↗

bioRxiv2024

A multi-omics and cell type-specific characterization of the ventral striatum in human cocaine use disorder

Epigenome, transcriptome, and proteome analyses of postmortem brains have revealed initial molecular insights into cocaine use disorder (CUD). However, the inter-relationship between these -omics and the contribution of individual cell types remain largely unknown. We present an in-depth analysis of molecular changes in the ventral striatum in CUD at multi-omics and single-cell resolution. Integrative multi-omics analyses of microRNA-seq, RNA-seq, and proteomics datasets in 41 individuals and single-nuclei RNA-seq in a subset of 16 individuals revealed conserved deregulation of metabolic pathways, oxidative phosphorylation, and glutamatergic signaling. Cell type-specific analyses identified inverse metabolic pathway deregulation patterns in glial and neuronal cells, notably in astrocytes and medium spiny neurons (MSNs). Characterizing astrocyte-neuron crosstalk revealed altered glutamatergic and cell adhesion signaling in CUD. By applying a comprehensive multi-omics analytical framework, our study provides novel insights into CUD-associated molecular changes in the ventral striatum, suggesting astrocytes, MSNs, and their crosstalk as particularly perturbed in CUD.

neuroscience↗

bioRxiv2022

Capturing the pathomechanisms of different disease severities in a human cerebral organoid model of LIS1-lissencephaly

Lissencephaly is a malformation of cortical development (MCD) characterized by reduced to absent gyri and a disorganized cortex, leading to severe neurological consequences in affected individuals, including epilepsy, intellectual disability, and reduced life expectancy. Treatments are purely symptomatic, and patients often remain refractory to them. Heterozygous mutations in the LIS1 gene, encoding a regulator of the microtubule motor dynein, cause LIS1-lissencephaly. For unknown reasons, LIS1-lissencephaly patients show marked differences in disease severity despite each carrying a heterozygous LIS1 mutation. We leveraged forebrain-type organoids from patients diagnosed with mild, moderate, or severe LIS1-lissencephaly to investigate, in a cytoarchitecture and multi-omics approach, disease and severity grade associated phenotypes, mechanisms, and rescue approaches. We identified alterations of the cytoarchitecture, progenitor cell homeostasis, and neurogenesis often with a severity-dependent gradient. Identified disease-linked molecular mechanisms were microtubule destabilization, WNT-signaling, protein metabolism, and perturbed cadherin- and unfolded protein-binding. Some mechanisms exhibited a severity-dependent gradient or were specific to a severe grade. We present strategies to reverse phenotypic changes in LIS1-patient organoids and identify mTOR pathway inhibitors in in silico drug repurposing analysis as potential novel therapeutic strategy. By probing the top hit drug, the mTOR inhibitor everolimus, we could indeed rescue severity-dependent phenotypic changes in LIS1-patient organoids. This study demonstrates that organoid-based modeling is sensitive in recapitulating disease severity, which presents an important step in patient stratification, and allows the development of novel personalized rescue strategies with therapeutic potential.

neuroscience↗

bioRxiv2021

Real-time individual benefit from social interactions before and during the lockdown: The crucial role of personality, neurobiology and genes.

BackgroundSocial integration is a major resilience factor for staying healthy. However, the COVID-19-pandemic led to unprecedented restrictions in social life. The consequences of these social lockdowns on momentary well-being are yet not fully understood. MethodWe investigated the individual affective benefit from social interactions in a longitudinal birth cohort study. We used two real-time, real-life ecological momentary assessments once before and once during the initial lockdown of the pandemic (N~6800 total observations) to determine the protective role of social interactions on well-being. Moreover, we used a multimethod approach combining the ecological assessment data with individual risk and resilience factors to analyze the moderating mechanisms of personality, neurobiology and genes. ResultsSocial contacts were linked to higher positive affect both during normal times and during the COVID-19 pandemic, highlighting the beneficial role of social embedding. Moreover, this relationship was moderated by amygdala volume, neuroticism and polygenic risk for schizophrenia. In detail, participants with a larger left amygdala volume and higher trait neuroticism exhibited an affective benefit from more social interactions prior to the pandemic. This pattern changed during the pandemic with participants with smaller amygdala volumes and lower neurotic traits showing a social affective gain during the pandemic. Moreover, participants with low genetic risk for schizophrenia showed an affective benefit from social interactions irrespective of the time point. ConclusionOur results highlight the protective role of social integration on momentary well-being. Thereby, we offer new insights into how this relationship is differently affected by a persons, neurobiology, personality, and genes under adverse circumstances.

neuroscience↗