DNA-sequence and epigenomic determinants of local rates of transcription elongation.

Across all branches of life, transcription elongation is a crucial, regulated phase in gene expression. Many recent studies in eukaryotes have focused on the regulation of promoter-proximal pausing of RNA Polymerase II (Pol II), but rates of productive elongation also vary substantially throughout the gene body, both within and across genes. Here, we introduce a probabilistic model for systematically evaluating potential determinants of the local elongation rate based on nascent RNA sequencing (NRS) data. Our model is derived from a unified model for both the kinetics of Pol II movement along the DNA template and the generation of NRS read counts at steady state. It allows for a continuously variable elongation rate along the gene body, with the rate at each nucleotide defined by a generalized linear relationship with nearby genomic and epigenomic features. High-dimensional feature vectors are accommodated through a sparse-regression extension. We show with simulations that the model allows accurate detection of associated features and accurate prediction of local elongation rates. In an analysis of public PRO-seq and epigenomic data, we identify several features that are strongly associated with reductions in the local elongation rate, including DNA methylation, splice sites, RNA stem-loops, CTCF binding sites, and several histone marks, including H3K36me3 and H4K20me1. By contrast, low-complexity sequences and H3K79me2 marks are associated with increases in elongation rate. In an analysis of DNA