Characterization of sequence determinants of enhancer function using natural genetic variation

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• Sequence variations in enhancers significantly contribute to human phenotypic diversity.
• Predicting the functional impact of enhancer sequence variants on gene transcription is challenging due to complex transcription factor (TF) binding dynamics.

Purpose of the Study:

• To comprehensively assess allele-specific TF binding and enhancer function.
• To understand how sequence changes at enhancers influence their function across evolutionary time.

Main Methods:

• Utilized F1-hybrid cells from crosses between distinct mouse strains.
• Identified thousands of enhancers exhibiting allele-specific TF binding and/or activity.

Main Results:

• Genetic variants within enhancer central regions most frequently alter TF binding and enhancer activity.
• AP-1 family TFs (Fos/Jun) are often crucial for TEAD TF binding and enhancer function.
• Sequence variants outside core TF motifs, including flanking regions and AP-1 half sites, also impact enhancer function.

Conclusions:

• This study provides a detailed assessment of allele-specific TF binding and enhancer function.
• Reveals the mechanisms by which sequence variations at enhancers modulate gene regulation across evolutionary scales.