Differential L1 regulation in pluripotent stem cells of humans and apes

Abstract

Summary Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic understanding of the evolution and diversity of our own species. Until now, preserved tissues have been the main source for most comparative studies between humans, chimpanzees ( Pan troglodytes ) and bonobos ( Pan paniscus ) 1 , 2 . However, these tissue samples do not fairly represent the distinctive traits of live cell behavior and are not amenable to genetic manipulation. We hypothesized that induced pluripotent stem cells (iPSCs) could be a unique biological resource to elucidate relevant phenotypical differences between human and NHPs and that those differences could have potential adaptation and speciation value. Here, we describe the generation and initial characterization of iPSCs from chimpanzees and bonobos as novel tools to explore factors that have contributed to great ape evolution. Comparative gene expression analysis of human and NHP iPSCs revealed differences in the regulation of Long Interspersed Nuclear Element-1 (LINE-1 or L1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution 3 - 5 . Decreased levels of L1 restricting factors APOBEC3B (A3B) 6 and PIWIL2 7 in NHP iPSCs correlated with increased L1 mobility and endogenous L1 mRNA levels. Moreover, results from manipulation of A3B and PIWIL2 levels in iPSCs supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPSCs in culture and may have also occurred in the germline or embryonic cells developmentally upstream to germline specification during primate evolution. We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have ongoing adaptive significance.

Present and future challenges of induced pluripotent stem cells

“…Their iPSCs, which are derived from fibroblasts or blood cells which are relatively easy to obtain, have made it possible to analyse and compare interspecies cells in vitro. The comparison of humans and apes has revealed human-specific traits in the regulation mechanisms of LINE-1 transposons [121]. Although the iPSC-facilitated study of evolution and development has just begun, the iPSCs in those fields offer huge potential in elucidating the processes by which living things obtained diversity and complexity.…”

Insights in human epigenomic dynamics through comparative primate analysis

“…The role of repeat classes within these species-specific enhancers was also noted, with endogenous retroviruses (ERV1, ERVL-MaLR, and ERVK) as well as L1 elements (LINE-1 retrotransposons) particularly enriched within these loci. Evidence of variation in the regulation of the primate-active L1s in pluripotent stem cells between humans and other apes is proposed to have differentially shaped these genomes [75].…”

Stress and the dynamic genome: Steroids, epigenetics, and the transposome

“…Gage and coworkers have argued that this retrotransposon-induced mosaicism permits increased neuronal diversity in analogy with the retrotransposon-derived V(D)J recombination system that drives antibody diversity in the immune system (97), which is one of the best-described and understood examples of the adaptive value of the transposition machinery (98)(99)(100). In this vein, it is interesting to note that there are substantial differences in the regulation of stem-cell L1 elements in humans and apes (101). Although the capacity of these elements to produce neuronal diversity through transposition is clear, it is likely that this genotypic diversity is not the only means by which these elements contribute to brain function.…”