Regulatory networks of KRAB zinc finger genes and transposable elements changed during human brain evolution and disease

Abstract

Transposable elements (TEs), with their ability to change positions within a genome, have paradoxically been seen as both a potentially deleterious genomic phenomenon and a potent driving force behind evolution. The genome-protecting KRAB zinc finger (KRAB-ZNF) proteins play a critical role in repressing TE expression within mammalian genomes, engaging in a dynamic interplay. This interplay was suggested to evolve according to an arms-race model, wherein TEs strive to transpose within the genome and KRAB-ZNFs adapt to suppress them. Despite indications of the involvement of TEs and KRAB-ZNFs in brain evolution and disease, a systematic analysis of their interactions is still lacking. In this study, we explored the functional connections between KRAB-ZNFs and TEs in the context of human brain evolution and Alzheimer’s disease (AD). We conducted an analysis of KRAB-ZNF genes and TEs expression patterns and networks using two independent RNA-seq datasets: (1) data from 33 human and multiple non-human primate brain regions, and (2) data from the temporal cortex and cerebellum of both healthy individuals and AD patients. To efficiently compare the regulatory networks across species, we developed the TEKRABber R package, which enables estimating TE and KRAB-ZNF expression levels and pairwise correlations between them, facilitating cross-species regulatory network comparisons. Our analysis highlighted species-specific expression variations, with many recently evolved TEs and KRAB-ZNF genes being differentially expressed between species, emphasizing their impact on evolution. Focusing on one-to-one negative correlations between TEs and KRAB-ZNF genes (negative TE:KRAB-ZNF), we found that many of those correlations engage recently evolved TEs and KRAB-ZNF genes and are specific to humans. Integrating findings from the second dataset, we identified 2492 human-specific negative TE:KRAB-ZNF pairs uniquely detectable in the healthy human temporal cortex, suggesting dysregulation in AD brains. A distinct subcluster in the network formed by these 2492 pairs consists of Alu elements, underscoring their unique role in human brain evolution and disease. Our results deepens insights into primate brain evolution and offer a new perspective on human neurodegenerative disease through the analysis of the negative TE:KRAB-ZNF regulatory network.Graphical Abstract