LINE-1 retrotransposon activation intrinsic to interneuron development

Abstract

Transposable elements (TEs) are a reservoir of new transcription factor binding sites for protein-coding genes. Developmental programs that activate TE-derived regulatory elements could, in principle, manifest in lineage-specific TE mobility. While somatic LINE-1 (L1) retrotransposon insertions have been detected in human neurons, the impact of L1 insertions on neurodevelopmental gene regulation, and whether L1 mobility is restricted to certain neuronal lineages, is unknown. Here, we reveal programmed L1 activation by SOX6, a transcription factor critical for parvalbumin (PV+) interneuron development. PV+ neurons harbor unmethylated and euchromatic L1 promoters, express L1 mRNA, and permit L1 transgene mobilization in vivo. Elevated L1 expression in adult dentate gyrus PV+ neurons is however attenuated by environmental enrichment. Nanopore sequencing of PV+ neurons identifies unmethylated L1 loci providing alternative promoters to core PV+ neuron genes, such as CAPS2. These data depict SOX6-mediated L1 activation as an ingrained component of the mammalian PV+ neuron developmental program.

Somatic retrotransposition in the developing rhesus macaque brain

“…Although L1RS somatic was detected by PCR at its 5′ or 3′ genomic junction in 5/72 MDA-amplified neurons from ON22213, and in bulk hippocampus, the complete insertion could only be PCR-amplified in neuron #15. Furthermore, we analyzed a pan-neuronal (RBFOX3 + ) hippocampal population, which could obscure potential sublineage-specific L1 activity ( Faulkner and Garcia-Perez 2017 ; Bodea et al 2022 ). These considerations in our view prohibit an accurate calculation of L1 mobilization frequency in the macaque brain, extrapolated from one bona fide somatic L1RS2 insertion.…”