Exonic enhancers are a widespread class of dual-function regulatory elements

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• Gene regulation is complex, involving various DNA elements.
• Exonic enhancers (EEs) are a newly recognized class of regulatory elements.
• Their function and prevalence were previously under-appreciated.

Purpose of the Study:

• To investigate the regulatory role of protein-coding exons.
• To identify and characterize exonic enhancers (EEs) across species.
• To explore the involvement of EEs in gene expression and disease.

Main Methods:

• Integration of transcription factor binding data, chromatin accessibility, and enhancer-reporter assays.
• Epigenomic profiling and long-range interaction analyses.
• CRISPR-mediated inactivation and large-scale cancer genome analyses.

Main Results:

• Many protein-coding exons exhibit enhancer activity (candidate EEs or cEEs).
• cEEs possess distinct epigenomic signatures and interact with promoters.
• cEEs are affected by genetic variants and play roles in cis-regulation.
• Mutations in cEEs correlate with altered gene expression and clinical outcomes in cancer.
• Evolutionary analysis reveals conserved and lineage-specific features of cEEs.

Conclusions:

• Exonic enhancers are functional regulatory elements with dual roles in coding and regulation.
• cEEs are involved in cis-regulation of gene expression and disease.
• These findings expand the known repertoire of functional genomic elements.