# MER57E3 transposable elements regulate gene expression in a human cell model of neural development

## TL;DR

This study shows that MER57E3 transposable elements help regulate gene expression during human neural development, potentially impacting neurodevelopmental disorders.

## Contribution

The study identifies MER57E3 as a regulatory element in neural development through epigenetic profiling and CRISPRi experiments.

## Key findings

- MER57E3 elements show active histone modifications in human neural cell types.
- MER57E3 is enriched near zinc finger genes and homeodomain motifs recognized by brain-specific transcription factors.
- CRISPRi targeting MER57E3 leads to downregulation of neurogenesis-related genes PAX6 and NEUROG2.

## Abstract

Long dismissed as mere genomic parasites, transposable elements (TEs) are now recognized as major drivers of genome evolution. TEs serve as a source of cell-type specific cis-regulatory elements, influencing gene expression and observable phenotypes. However, the precise TE regulatory roles in different contexts remain largely unexplored and the impact of TEs on transcriptional regulatory networks and contribution to disease risk is likely deeply underestimated.

Using a multimapper-aware strategy, we systematically characterize the epigenetic profile of TEs in human cell systems modeling neural development. This analysis reveals that MER57E3, a primate-specific TE subfamily, exhibits strong enrichment for active, and absence of repressive, histone modifications across six cultured human neural cell types. MER57E3 copies are predominantly located near zinc finger genes and enriched for homeodomain motifs recognized by brain-specific transcription factors, including GBX1 and BSX. Upon CRISPR interference (CRISPRi) targeting specific MER57E3 copies, RNA-seq analysis demonstrates downregulation of the key neurogenesis-related genes PAX6 and NEUROG2.

Our data indicate that members of the MER57E3 TE subfamily regulate the expression of critical neurogenesis genes during neural progenitor cell (NPC) development. Moreover, this study emphasizes the importance of investigating TEs, offering new insights into how their epigenetic dysregulation may contribute to pathogenesis of neurodevelopmental disorders.

The online version contains supplementary material available at 10.1186/s13059-026-03946-x.