Biology subjects

Sportelli, V.

Publications and source records attributed to Sportelli, V..

3 recordsLinked to original sources

bioRxiv2024

Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids

Disruptions in the tightly regulated process of human brain development have been linked to increased risk for brain and mental illnesses. While the genetic contribution to these diseases is well established, important environmental factors have been less studied at molecular and cellular levels. In this study, we used single-cell and cell-type-specific techniques to investigate the effect of glucocorticoid (GC) exposure, a mediator of antenatal environmental risk, on gene regulation and lineage specification in unguided human neural organoids. We characterized the transcriptional response to chronic GC exposure during neural differentiation and studied the underlying gene regulatory networks by integrating single-cell transcriptomics-with chromatin accessibility data. We found lasting cell type-specific changes that included autism risk genes and several transcription factors associated with neurodevelopment. Chronic GCs influenced lineage specification primarily by priming the inhibitory neuron lineage through key transcription factors like PBX3. We provide evidence for convergence of genetic and environmental risk factors through a common mechanism of altering lineage specification.

neuroscience↗

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↗

bioRxiv2022

Temporal regulation of ZBTB16 expression by glucocorticoids alters human cortical neurogenesis

Glucocorticoids are important for proper organ maturation and their levels are tightly regulated during development. Here we use human cerebral organoids and mice to study cell-type specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to drive cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels, reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is supported by data from a prospective pregnancy cohort. This study provides a novel cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes.

neuroscience↗