Biology subjects

Vangelisti, S.

Publications and source records attributed to Vangelisti, S..

5 recordsLinked to original sources

bioRxiv2025

Neural stem cell epigenomes and fate bias are temporally coordinated during corticogenesis

The cerebral cortex orchestrates complex cognitive functions, yet how its distinct temporal lineages are molecularly patterned during development remains unresolved. Here, we integrate single-cell transcriptomics and chromatin accessibility, together with genome-wide profiling of DNA methylation and 3D chromosomal contact across mouse corticogenesis (E13-E18) to elucidate cell fate transitions. Using metacell flow analysis, we reveal that neural stem cells (NSCs) progressively shift from a progenitor-biased state toward an astrocytic lineage and that this process is accompanied with changes in DNA methylation and 3D genome organization. A model integrating transcription factor motif affinities with epigenetic features identifies key regulators of cis-regulatory element (CRE) activation. In vivo reporter assays further decouple the intrinsic regulatory potential of CREs from context-dependent synergistic activation. Collectively, our findings uncover temporal epigenomic reprogramming that underlies the evolving differentiation potential of NSCs, providing insights into the intrinsic and extrinsic mechanisms that pattern cortical lineages.

genomics↗

bioRxiv2025

Human-specific morphoregulatory signatures in basal radial glia characterize neocortex evolution

As the seat of our cognition, the human neocortex is an object of immense fascination. Human neocortex expansion during evolution has been attributed to an increase in the proliferative capacity of neural progenitor cells during development, particularly basal radial glia (bRG). Despite their evolutionary relevance, the genomic changes driving human-specific bRG biology remain uncharacterized. We used comparative chromatin and transcriptional profiling of neural progenitor cells isolated from gorilla, chimpanzee and human cerebral organoids to identify cis-regulatory elements that have gained activity in humans. Focusing specifically on bRG, we discovered that morphoregulatory enhancer activity and gene expression signatures distinguish human bRG from other great apes. Functional analysis of the morphoregulatory genes FAM107A and CNGA3 in human organoids revealed that these genes are required for the morphological complexity of human bRG. Taken together, our interspecies comparison of basal radial glia suggests that human-specific morphoregulatory signatures characterize neocortex evolution.

neuroscience↗

bioRxiv2025

3D Epigenome Evolution Underlies Divergent Gene Regulatory Programs in Primate Neural Development

The expansion of the neocortex is a hallmark of human evolution and is closely linked to neural stem cell biology. Yet, the epigenetic mechanisms driving divergent gene regulation during primate neurogenesis remain elusive. Here, we comprehensively mapped 3D genome organization, chromatin accessibility and gene expression in induced pluripotent stem cells and derived neural stem cells from human, chimpanzee, gorilla and macaque. We identified human-specific epigenetic signatures including cis-regulatory regions and enhancer-promoter interactions and linked them to gene regulatory dynamics. Deep learning models revealed that complex regulatory grammar at cis-regulatory regions, including transcription factor binding sites, local context and higher-order chromatin organization, underlies species and cell type-specific differences. High-resolution Hi-C uncovered unexpected global shifts in 3D genome architecture in chimpanzee and gorilla neural stem cells while topologically associating domains remain remarkably conserved. Notably, species-specific genes interacted with multiple differentially accessible regions, suggesting that synergistic enhancer activation is a key mechanism driving epigenome evolution. These findings provide new insights into the epigenetic basis of primate brain evolution.

genomics↗

bioRxiv2020

Multiomics analysis reveals extensive epigenome remodeling during cortical development

Despite huge advances in stem-cell, single-cell and epigenetic technologies, the precise molecular mechanisms that determine lineage specification remain largely unknown. Applying an integrative multiomics approach, e.g. combining single-cell RNA-seq, single-cell ATAC-seq together with cell-type-specific DNA methylation and 3D genome measurements, we systematically map the regulatory landscape in the mouse neocortex in vivo. Our analysis identifies thousands of novel enhancer-gene pairs associated with dynamic changes in chromatin accessibility and gene expression along the differentiation trajectory. Crucially, we provide evidence that epigenetic remodeling generally precedes transcriptional activation, yet true priming appears limited to a subset of lineage-determining enhancers. Notably, we reveal considerable heterogeneity in both contact strength and dynamics of the generally cell-type-specific enhancer-promoter contacts. Finally, our work suggests a so far unrecognized function of several key transcription factors which act as putative "molecular bridges" and facilitate the dynamic reorganization of the chromatin landscape accompanying lineage specification in the brain.

genomics↗

bioRxiv2018

LncRNA Spehd regulates hematopoietic stem cells and progenitors and is required for multilineage differentiation

Long non-coding RNAs (lncRNAs) show patterns of tissue- and cell-type-specific expression that are very similar to those of protein coding genes and consequently have the potential to control stem and progenitor cell fate decisions along a differentiation trajectory. To understand the roles that lncRNAs might play in hematopoiesis, we selected a subset of mouse lncRNAs with potentially relevant expression patterns and refined our candidate list using evidence of conserved expression in human blood lineages. For each candidate, we assessed its possible role in hematopoietic differentiation in vivo using competitive transplantation. Our studies identified two lncRNAs that were required for hematopoiesis. One of these, Spehd, showed defective multi-lineage differentiation, and its silencing yielded common myeloid progenitors deficient in their oxidative phosphorylation pathway. This effort not only suggests that lncRNAs can contribute to differentiation decisions during hematopoiesis but also provides a path toward the identification of functional lncRNAs in other differentiation hierarchies.

molecular biology↗