128: LINE‑1 Promoters Orchestrate Early Human Brain Development

️ Episode 128: LINE‑1 Promoters Orchestrate Early Human Brain Development

In this episode of PaperCast Base by Base, we explore how evolutionarily young LINE‑1 retrotransposons are actively expressed in human induced pluripotent stem cells and function as cis‑acting promoters that shape primate‑ and human‑specific transcript isoforms during early neural differentiation.

Study Highlights:
The authors combine short‑ and long‑read RNA‑seq with CUT&RUN epigenomic profiling and long‑read DNA methylation analysis to map thousands of unique L1 loci expressed in hiPSCs and early cerebral organoids. L1 promoter activity correlates with H3K4me3 enrichment and hypomethylation, and the L1‑derived protein ORF1p is abundant in hiPSCs. Using an optimized KRAB‑dCas9 CRISPR interference system targeting the 5′ UTR, they achieve on‑target silencing of young, full‑length L1s and uncover nearly a hundred L1‑driven chimeric transcripts, including alternative promoter isoforms for protein‑coding genes such as ELAPOR2, PPP1R1C, and PLCB1. In cerebral organoids, L1 expression is globally reduced with differentiation‑coupled remethylation yet remains locus‑specific and variable, and L1 silencing shifts neural progenitor transcriptional programs and yields smaller organoids without altering overall cell‑type composition.

Conclusion:
LINE‑1 promoters provide a hominoid‑specific regulatory layer that tunes the exit from pluripotency and the tempo of early human brain development, with implications for human brain evolution and neurodevelopmental disease mechanisms.

Reference:
Adami A, Garza R, Gerdes P, Johansson PA, Dorazehi F, Koutounidou S, Castilla‑Vallmanya L, Atacho DAM, Sharma Y, Johansson JG, Tam O, Kirkeby A, Barker RA, Hammell MG, Douse CH, Jakobsson J. LINE‑1 retrotransposons mediate cis‑acting transcriptional control in human pluripotent stem cells and regulate early brain development. Cell Genomics. 2025;5:100979. https://doi.org/10.1016/j.xgen.2025.100979

License:
This episode is based on an open‑access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Keywords: LINE‑1 retrotransposons; alternative promoters; cerebral organoids; human iPSCs; neural differentiation