Comparing great apes reveals human-specific ZEB2 roles in neural development

Area of Science:

• Evolutionary biology
• Genomics
• Neuroscience

Background:

• Human evolution is marked by traits distinct from other primates, despite similar protein-coding genes.
• Transcriptional regulation is key to understanding the evolution of these human-specific traits.
• The transcription factor ZEB2 plays a critical role in immune and neural development.

Purpose of the Study:

• To investigate the regulatory divergence of ZEB2 across great apes.
• To identify human-specific gene targets regulated by ZEB2.
• To understand how ZEB2 regulatory shifts contribute to phenotypic evolution.

Main Methods:

• Utilized B-lymphoblastoid cells from humans, chimpanzees, and orangutans.
• Performed ZEB2 knock-down experiments followed by transcriptome profiling.
• Analyzed single-cell RNA-Seq and brain organoid data.

Main Results:

• Human ZEB2 regulates a distinct set of genes, particularly those involved in neuronal development, compared to other apes.
• Human-specific ZEB2 targets are enriched in non-coding genes, indicating a rewired regulatory network.
• Cell-type-specific differences in ZEB2 expression and target genes were observed, especially in neural progenitors and neurons.

Conclusions:

• Species differences in ZEB2 regulation are detectable in cell systems and validated in neural contexts.
• ZEB2 regulatory divergence offers insights into the evolution of transcription factors and phenotypic changes.
• Shifts in transcriptional regulation, exemplified by ZEB2, are crucial for understanding human evolutionary divergence.