Compatibility rules of human enhancer and promoter sequences

Area of Science:

• Genomics and Gene Regulation
• Molecular Biology
• Epigenetics

Background:

• Gene regulation in the human genome relies on distal enhancers activating specific promoters.
• The 'biochemical compatibility' model suggests sequence-encoded preferences between enhancers and promoters mediate specificity.
• Previous studies supported this model in individual promoters and in Drosophila, but systematic measurement in humans was lacking.

Purpose of the Study:

• To systematically measure the intrinsic compatibility between human enhancers and promoters.
• To understand how enhancer and promoter activities combine to control RNA expression.
• To identify rules governing enhancer-promoter interactions in human cells.

Main Methods:

• Development and application of a high-throughput reporter assay: enhancer × promoter self-transcribing active regulatory region sequencing (ExP STARR-seq).
• Examination of combinatorial compatibilities between 1,000 enhancer and 1,000 promoter sequences.
• Analysis of gene transcription control in human K562 cells.

Main Results:

• Identification of simple rules for enhancer-promoter compatibility: most enhancers activate all promoters similarly.
• Intrinsic enhancer and promoter activities multiplicatively combine to determine RNA output (R² = 0.82).
• Two classes of enhancers and promoters exhibit subtle preferential effects; housekeeping gene promoters are less responsive to enhancers due to built-in motifs (GABPA, YY1).

Conclusions:

• A multiplicative model, tuned by enhancer and promoter class, governs gene transcription in the human genome.
• Housekeeping gene promoters possess intrinsic features reducing distal enhancer responsiveness.
• Variably expressed gene promoters lack these features, showing stronger enhancer responsiveness.