Allelic Transcription Factor binding shape transcriptional kinetics in human cell lines

Gene expression from bulk RNA-seq studies is an average measurement between two chromosomes and across cell populations. Both allelic and cell-to-cell heterogeneity in gene expression results from promoter bursting patterns that repeatedly alternate between an activated and inactivated state. Increased cell-to-cell heterogeneity in gene expression has been associated with aging and stem cell pluripotency. However, studies of bursting kinetics and their molecular mechanism are relatively limited in human cells compared to other species due to laborious single-molecule experiments. Here, we systematically investigate the regulatory effect of genetic variants and transcription factor (TF) binding on transcriptional kinetics at the single chromosome level with GM12878. We found that the transcription initiation rate and burst frequency correlate most with eQTL effect sizes among transcriptional kinetics, which suggests that eQTLs affect average gene expression mainly through altering burst kinetics. We further found that [~]90% of the variance of burst frequency can be explained by TF occupancy in phase with the core promoter. We identified and replicated several examples where eQTL or GWAS catalog loci perturb TF binding affinity and are consequently associated with the change of burst kinetics.