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

Area of Science:

• Genomics
• Epigenetics
• Neuroscience

Background:

• Transposable elements (TEs), once viewed as genomic parasites, are now recognized as key drivers of genome evolution.
• TEs contribute cell-type specific cis-regulatory elements that influence gene expression and phenotypes.
• The regulatory roles and disease implications of TEs, particularly in transcriptional networks, are likely underestimated.

Purpose of the Study:

• To systematically characterize the epigenetic profile of TEs in human neural development models.
• To investigate the regulatory function of specific TE subfamilies, like MER57E3, in neurogenesis.
• To explore the potential contribution of TE epigenetic dysregulation to neurodevelopmental disorders.

Main Methods:

• Utilized a multimapper-aware strategy for systematic TE epigenetic profiling in human neural cell systems.
• Analyzed histone modifications and transcription factor motif enrichment associated with TEs.
• Employed CRISPR interference (CRISPRi) and RNA-sequencing (RNA-seq) to assess the impact of TE targeting on gene expression.

Main Results:

• Identified MER57E3, a primate-specific TE subfamily, as enriched for active histone modifications in six human neural cell types.
• Found MER57E3 copies located near zinc finger genes and enriched for brain-specific transcription factor binding motifs (e.g., homeodomain motifs).
• Demonstrated that CRISPRi-mediated targeting of MER57E3 copies leads to downregulation of neurogenesis genes PAX6 and NEUROG2.

Conclusions:

• MER57E3 transposable elements regulate key neurogenesis genes during neural progenitor cell development.
• Highlights the significance of studying TEs and their epigenetic regulation in understanding neurodevelopment.
• Suggests that epigenetic dysregulation of TEs may contribute to the pathogenesis of neurodevelopmental disorders.