Coding exons function as tissue-specific enhancers of nearby genes.

Area of Science:

• Genomics
• Molecular Biology
• Developmental Biology

Background:

• Enhancers are crucial gene regulatory elements, but current identification methods often overlook protein-coding regions.
• Alterations in enhancers can cause developmental abnormalities and human diseases.

Purpose of the Study:

• To investigate the potential enhancer function of sequences overlapping coding exons.
• To explore the dual role of DNA sequences as both coding exons and regulatory elements.

Main Methods:

• Analysis of ChIP-seq data (H3K4me1, H3K27ac, EP300) for overlaps with coding exons.
• Enhancer assays in mouse and zebrafish to test exonic enhancer (eExon) activity.
• Chromatin conformation capture (3C) and DNA fluorescence in situ hybridization (FISH) to study enhancer-promoter interactions.

Main Results:

• Approximately 7% of enhancer ChIP-seq peaks overlap with coding exons (excluding first exons).
• Several identified eExons demonstrated enhancer activity for neighboring genes, with the exonic sequence being essential.
• A specific limb enhancer (Dync1i1 exon 15) interacts with the Dlx5/6 promoter, and its disruption is linked to SHFM1.

Conclusions:

• DNA sequences can possess dual functions, acting as coding exons in some contexts and enhancers in others.
• This dual role suggests that mutations in coding exons could disrupt gene regulation, contributing to disease phenotypes.
• The findings expand the understanding of gene regulation and the genetic basis of developmental disorders.