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Inference of RNA polymerase II transcription dynamics from chromatin immunoprecipitation time course data.

Published version
Peer-reviewed

Type

Article

Change log

Authors

wa Maina, Ciira 
Honkela, Antti 
Matarese, Filomena 
Grote, Korbinian 
Stunnenberg, Hendrik G 

Abstract

Gene transcription mediated by RNA polymerase II (pol-II) is a key step in gene expression. The dynamics of pol-II moving along the transcribed region influence the rate and timing of gene expression. In this work, we present a probabilistic model of transcription dynamics which is fitted to pol-II occupancy time course data measured using ChIP-Seq. The model can be used to estimate transcription speed and to infer the temporal pol-II activity profile at the gene promoter. Model parameters are estimated using either maximum likelihood estimation or via Bayesian inference using Markov chain Monte Carlo sampling. The Bayesian approach provides confidence intervals for parameter estimates and allows the use of priors that capture domain knowledge, e.g. the expected range of transcription speeds, based on previous experiments. The model describes the movement of pol-II down the gene body and can be used to identify the time of induction for transcriptionally engaged genes. By clustering the inferred promoter activity time profiles, we are able to determine which genes respond quickly to stimuli and group genes that share activity profiles and may therefore be co-regulated. We apply our methodology to biological data obtained using ChIP-seq to measure pol-II occupancy genome-wide when MCF-7 human breast cancer cells are treated with estradiol (E2). The transcription speeds we obtain agree with those obtained previously for smaller numbers of genes with the advantage that our approach can be applied genome-wide. We validate the biological significance of the pol-II promoter activity clusters by investigating cluster-specific transcription factor binding patterns and determining canonical pathway enrichment. We find that rapidly induced genes are enriched for both estrogen receptor alpha (ERα) and FOXA1 binding in their proximal promoter regions.

Description

Keywords

Animals, Chromatin Immunoprecipitation, Computer Simulation, DNA-Directed RNA Polymerases, Humans, Models, Genetic, Models, Statistical, Promoter Regions, Genetic, Protein Binding, Transcription, Genetic, Transcriptional Activation

Journal Title

PLoS Comput Biol

Conference Name

Journal ISSN

1553-734X
1553-7358

Volume Title

10

Publisher

Public Library of Science (PLoS)
Sponsorship
European Commission (305626)