Natural genetic variation determines promoter shape, affecting robustness of gene expression

SCHOR IE; CANNAVÒ E; HARNETT D; STEGLE O; GARFIELD DA; DEGNER JF; CASALE FP; FURLONG EE

Córdoba

Congreso; LII Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2016

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB)

Promoters act as platforms for converging cis-regulatory cues, which regulate the initiation of gene expression. Metazoan core promoters have characteristic distributions of transcriptional start sites (TSS), a feature called promoter shape. Although fundamental to understanding transcriptional initiation, the genetic determinants and functional differences between promoters with different shapes remain unclear. Here, we measured TSS usage across a panel of 81 Drosophila lines, identifying thousands of thousands of promoters where promoter strength and/or shape are modulated by common genetic variants. Our results identify promoter shape as a variable trait, evolvable independently of promoter strength. Broad promoters, typical of housekeeping genes, show an increase in the number of genetic variants affecting transcription. Since these variants have lower impact in promoter strength than those of narrow promoters, broad promoters appear as intrinsically more robust to genetic variation. By using single-cell expression analysis, we show that shape-shift mutations frequently increase expression noise, while other variants within the same promoter can alleviate these effects, often through epistatic interactions. This study uncovers new functional properties of natural promoters, and proposes the minimization of noise as an important factor influencing promoter evolution.