Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Abstract

Transposable elements (TEs) account for more than 50% of the human genome and many have been co-opted throughout evolution to provide regulatory functions for gene expression networks. Several lines of evidence suggest that these networks are fine-tuned by the largest family of TE controllers, the KRAB-containing zinc finger proteins (KZFPs). One tissue permissive for TE transcriptional activation (termed “transposcription”) is the adult human brain, however comprehensive studies on the extent of this process and its potential contribution to human brain development are lacking. To elucidate the spatiotemporal transposcriptome of the developing human brain, we have analyzed two independent RNA-seq data sets encompassing 16 brain regions from eight weeks postconception into adulthood. We reveal a distinct KZFP:TE transcriptional profile defining the late prenatal to early postnatal transition, and the spatiotemporal and cell type–specific activation of TE-derived alternative promoters driving the expression of neurogenesis-associated genes. Long-read sequencing confirmed these TE-driven isoforms as significant contributors to neurogenic transcripts. We also show experimentally that a co-opted antisense L2 element drives temporal protein relocalization away from the endoplasmic reticulum, suggestive of novel TE dependent protein function in primate evolution. This work highlights the widespread dynamic nature of the spatiotemporal KZFP:TE transcriptome and its importance throughout TE mediated genome innovation and neurotypical human brain development. To facilitate interactive exploration of these spatiotemporal gene and TE expression dynamics, we provide the “Brain TExplorer” web application freely accessible for the community.

Transposable elements contribute to the spatiotemporal microRNA landscape in human brain development

“…3A). These data suggest that the CB exhibits, not only different TE and gene expression compared to other brain regions as previously described (Playfoot et al 2021;Li et al 2018), but also differences in TE-embedded miRNA expression.…”

Young transposable elements rewired gene regulatory networks in human and chimpanzee hippocampal intermediate progenitors

“…Moreover, SVAs are among the few transposable elements that still exhibit active transposition in the human genome. We and others have previously revealed that SVAs can be source of enhancers in primates (Playfoot et al, 2021; Pontis et al, 2019; Trizzino et al, 2017; Trizzino et al, 2018). The repression of some SVAs by specific zinc-finger proteins at specific stages of neuronal development is also a crucial mechanism for successful neurogenesis (Playfoot et al, 2021; Pontis et al, 2019; Turelli et al, 2020).…”

“…We and others have previously revealed that SVAs can be source of enhancers in primates (Playfoot et al, 2021; Pontis et al, 2019; Trizzino et al, 2017; Trizzino et al, 2018). The repression of some SVAs by specific zinc-finger proteins at specific stages of neuronal development is also a crucial mechanism for successful neurogenesis (Playfoot et al, 2021; Pontis et al, 2019; Turelli et al, 2020). Here, we demonstrate that SVAs are pervasive regulators of hippocampal neurogenesis and they act as enhancers in the hippocampal intermediate progenitor population.…”

Non‐coding regulatory elements: Potential roles in disease and the case of epilepsy

“…TEs that are still mobile within an individual's genome mobilise predominantly in germ cells and during early embryogenesis [30,31]. Since TEs often include TSSs and other regulatory sequences in their own sequence, their mobilisation has contributed to the formation of novel tissue-specific promoters and transcription factor binding sites (TFBSs), which now have a role in ensuring the correct spatiotemporal gene expression patterns during development [32,33]. Furthermore, TE mobilisation also occurs in somatic cells.…”