Quantifying the impact of genetic mutations on enhancer dynamics.

CRISPR/Cas9-mediated deletion of six transcription factors affects enhancer activity and gene expression in over 253,000 fragments, with 46,142 cell type-specific enhancers identified.

• Why it matters: Understanding how genetic mutations influence enhancer dynamics is crucial for deciphering transcriptional regulation and disease mechanisms, yet this relationship remains poorly characterized.
• What they did: The authors developed UDI-UMI-STARR-seq combined with RNA-seq to profile changes in enhancer activity and gene expression, applying it to assess the impact of deleting six transcription factors across a large enhancer dataset.
• The result: Responsive enhancer fragments linked to gene expression changes, including Wnt/p53 targets, and a deep learning model captured enhancer grammar, enabling scalable analysis of genetic perturbations like 16p12.1 deletion.