Dietl, T. | Search bioRxiv

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↗

bioRxiv2024

Identification and comparison of orthologous celltypes from primate embryoid bodies shows limits of marker gene transferability

The identification of cell types remains a major challenge. Even after a decade of single-cell RNA sequencing (scRNA-seq), reasonable cell type annotations almost always include manual non-automated steps. The identification of orthologous cell types across species complicates matters even more, but at the same time strengthens the confidence in the assignment. Here, we generate and analyze a dataset consisting of embryoid bodies (EBs) derived from induced pluripotent stem cells (iPSCs) of four primate species: humans, orangutans, cynomolgus, and rhesus macaques. This kind of data includes a continuum of developmental cell types, multiple batch effects (i.e. species and individuals) and uneven cell type compositions and hence poses many challenges. We developed a semi-automated computational pipeline combining classification and marker based cluster annotation to identify orthologous cell types across primates. This approach enabled the investigation of cross-species conservation of gene expression. Consistent with previous studies, our data confirm that broadly expressed genes are more conserved than cell type-specific genes, raising the question how conserved - inherently cell type-specific - marker genes are. Our analyses reveal that human marker genes are less effective in macaques and vice versa, highlighting the limited transferability of markers across species. Overall, our study advances the identification of orthologous cell types across species, provides a well-curated cell type reference for future in vitro studies and informs the transferability of marker genes across species.

cell biology↗