Neuronal diversity, essential for brain function, remains poorly understood. In the past decade, advances in single-cell genomics technology have revealed that mobile DNA elements, such as the Long-Interspersed Element 1 (LINE-1 or L1) contribute to this diversity. L1, active in various mammals, including humans, can mobilise or “jump” from one place in the genome to another via an RNA intermediate. L1 insertions, whether within or near genes, can impact gene expression in various ways. They can change chromatin structure, alter transcription, and affect pre-mRNA processing. Previous research indicates that neuronal differentiation provides a window for L1 mobilisation. However, it is still unclear if L1 activity prefers specific neuronal types and how L1 insertions impact neuronal biology.
Our work reveals that L1 mobilisation is stimulated by SRY-box transcription factor 6 (SOX6), which plays a key role in the transcriptional program of parvalbumin-expressing (PV+) interneurons. PV+ neurons exhibit unmethylated L1 promoters, increased L1 mRNA and protein expression and support L1 transgene mobilisation in vivo. Using long-read nanopore DNA sequencing, we identified unmethylated L1 promoter loci in PV+ genes, which remarkably can generate novel transcript isoforms important for neuronal function.
Our findings show that L1 activity is integrated into the transcriptional program of PV+ interneurons, regulating specific PV+ gene expression. This reveals a remarkable aspect of L1’s potential, demonstrating its capacity to enhance regulatory gene networks as promoters, thereby expanding neuronal transcriptomes. Given that over 17% of the human genome consists of L1 sequences, their incorporation into regulatory networks offers a vast reservoir of gene regulation material. This material may be crucial for fostering neuronal plasticity in a dynamic environment.