Biology subjects

Schneper, L.

Publications and source records attributed to Schneper, L..

4 recordsLinked to original sources

bioRxiv2025

Social isolation upregulates takeout expression in female Drosophila melanogaster to promote sucrose feeding

Drosophila melanogaster provides a model system to examine how environmental stress interacts with sex to induce changes in brain function and behavior. Previous research suggests that social isolation induces changes in gene expression that encode a starvation-like brain state and reduce sleep. However, the extent to which social isolation alters behaviors via sex-specific brain changes is unclear. Here, we use Drosophila melanogaster to explore sex differences in chronic social isolation-induced behavioral and transcriptomic changes. We focused on takeout (to), a gene encoding a putative juvenile hormone-binding protein, as a target that is upregulated solely in females following social isolation. Male and female adult flies were exposed to chronic social isolation, and multiple behavioral sex differences were identified through tests of activity, motivation, aggression, and sugar consumption. RNA-seq analysis also identified several candidate genes that were associated with sex differences in isolation-induced behavioral changes. Our findings suggest that social isolation is sufficiently stressful to reveal latent sex differences in behavior, despite having no impact on survival. To expression and sucrose consumption were upregulated exclusively in females following social isolation. Following to knockdown in to-expressing cells, sucrose consumption decreased in socially isolated females but increased in males. However, to knock down, to overexpression, and transformer knock down in neurons did not change sucrose-feeding behavior between control and isolated females. Overall, our results suggest that manipulating to expression influences sucrose-feeding in opposite directions between females and males following social isolation, and that isolation-induced to overexpression in non-neuronal cells in the brain or head may play a role in communicating information about females nutritional status to the brain. Additional roles for to in stress-related behaviors and behavioral sex differences should be explored, as well as whether to participates in signaling pathways that may be functionally conserved in human disorders. Author SummaryChronic stress contributes to detrimental health effects, but our understanding of how stress induces sex differences in brain gene expression and behavior is incomplete. Here, we use a combination of behavioral testing, RNA sequencing, and genetic manipulations in Drosophila melanogaster to explore how social isolation reveals latent sex differences in gene expression and stress-relevant behaviors. We found the most pronounced sex differences in behaviors related to feeding and motivation. RNA profiling revealed isolated female-specific upregulation of over 100 genes, with many of them relating to reproduction and energy metabolism. We manipulated expression of the candidate gene takeout (to) and found that downregulating to in all to-expressing cells decreases sucrose-feeding in isolated females but increases it in isolated males. Our results suggest that within a chronic stress context, sex-specific effectors in the head may regulate gene expression related to feeding and macronutrient choice to ensure that females prioritize survival over reproduction. Learning more about this system in flies could provide insight into functionally analogous pathways in humans that may be dysregulated in female-biased stress-related disorders.

neuroscience↗

bioRxiv2025

Epigenetic modifiers to treat retinal degenerative diseases

We have previously demonstrated the ability of inhibitors of LSD1 and HDAC1 to block rod degeneration, preserve vision, maintain rod-specific transcripts and downregulate those involved in inflammation, gliosis, and cell death in the rd10 mouse model of Retinitis Pigmentosa (RP). To extend our findings we tested the hypothesis that this effect was due to altered chromatin structure by using a range of inhibitors of chromatin condensation to prevent photoreceptor degeneration in the rd10 mouse model. We used inhibitors for G9A/GLP that catalyzes methylation of H3K9, for EZH2 that catalyzes trimethylation of H3K27, and compared them to the actions of inhibitors of LSD1 and HDAC. All the inhibitors decondense chromatin and all preserve, to different extents, retinas from degeneration in rd10 mice, but they act through different metabolic pathways. One group of inhibitors, modifiers for LSD1 and EZH2, demonstrate a high level of maintenance of rod-specific transcripts, activation of Ca+2 and Wnt signaling pathways with inhibition of antigen processing and presentation, immune response and microglia phagocytosis. Another group of inhibitors, modifiers for HDAC and G9A/GLP work through upregulation of NGF-stimulated transcription, while down-regulating genes belong to immune response, extracellular matrix, cholesterol signaling and programmed cell death. Our results provide robust support for our hypothesis that inhibition of chromatin condensation can be sufficient to prevent rod death in rd10 mice.

neuroscience↗

bioRxiv2024

Genome Instability Precedes Viral Integration in Human Papilloma Virus Transformed Tonsillar Keratinocytes

Approximately 70% of oropharyngeal squamous carcinomas (OPSCC) are associated with human papillomavirus (HPV). While HPV-positive (HPV+) OPSCC responds better to standard therapies and patients with HPV+ tumor generally have better outcomes than those with HPV-negative (HPV-) tumors, a subset of HPV+ patients do have poor outcomes. Our previous work suggested that tumors with integrated virus exhibit significantly greater genome wide genomic instability than those with only episomal viral genomes and patients with HPV+ OPSCC with episomal viral genomes had better outcomes. To explore the causal relation between viral integration and genomic instability, we have examined the time course of viral integration and genetic instability in tonsillar keratinocytes transformed with HPV16. HPV-infected human tonsil keratinocyte cell lines were continuously passaged and every fifth passage some cells were retained for genomic analysis. Whole genome sequencing and optical genomic mapping confirmed that virus integrated in five of six cell lines while remaining episomal in the sixth. In all lines genome instability occurred during early passages, but essentially ceased following viral integration but continued to occur later passages in the episomal line. To test tumorigenicity of the cell lines, cells were injected subcutaneously into the flanks of nude mice. A cell line with the integrated virus induced tumors following injection in the nude mouse while that with the episomal virus did not. We conclude that genomic instability is not the result of viral integration but likely promotes integration. Moreover, those transformants with episomal virus appear to be less tumorigenic than those with integrated virus.

cancer biology↗

bioRxiv2023

Measuring the long arm of childhood in real-time: Epigenetic predictors of BMI and social determinants of health across childhood and adolescence

Children who are socioeconomically disadvantaged are at increased risk for high body mass index (BMI) and multiple diseases in adulthood. The developmental origins of health and disease hypothesis proposes that early life conditions affect later-life health in a manner that is only partially modifiable by later-life experiences. Epigenetic mechanisms may regulate the influence of early life conditions on later life health. Recent epigenetic studies of adult blood samples have identified DNA-methylation sites associated with higher BMI and worse health (epigenetic-BMI). Here, we used longitudinal and twin study designs to examine whether epigenetic predictors of BMI developed in adults are valid biomarkers of child BMI and are sensitive to early life social determinants of health. Salivary epigenetic-BMI was calculated from two samples: (1) N=1,183 8-to-19-year-olds (609 female, mean age=13.4) from the Texas Twin Project (TTP), and (2) N=2,020 children (1,011 female) measured at 9 and 15 years from the Future of Families and Child Well-Being Study (FFCWS). We found that salivary epigenetic-BMI is robustly associated with childrens BMI (r=0.36 to r=0.50). Longitudinal analysis suggested that epigenetic-BMI is highly stable across adolescence, but remains both a leading and lagging indicator of BMI change. Twin analyses showed that epigenetic-BMI captures differences in BMI between monozygotic twins. Moreover, children from more disadvantaged socioeconomic status (SES) and marginalized race/ethnic groups had higher epigenetic-BMI, even when controlling for concurrent BMI, pubertal development, and tobacco exposure. SES at birth relative to concurrent SES best predicted epigenetic-BMI in childhood and adolescence. We show for the first time that epigenetic predictors of BMI calculated from pediatric saliva samples are valid biomarkers of childhood BMI that are sensitive to social inequalities. Our findings are in line with the hypothesis that early life conditions are especially important factors in epigenetic regulation of later life health. Research showing that health later in life is linked to early life conditions have important implications for the development of early-life interventions that could significantly extend healthy life span.

genomics↗