A signal–noise model for significance analysis of ChIP-seq with negative control

Han Xu, Lusy Handoko, Xueliang Wei, Chaopeng Ye, Jianpeng Sheng, Chia-Lin Wei, Feng Lin, Wing-Kin Sung
2010 Computer applications in the biosciences : CABIOS  
Motivation: ChIP-seq is becoming the main approach to the genome-wide study of protein-DNA interactions and histone modifications. Existing informatics tools perform well to extract strong ChIP-enriched sites. However, two questions remain to be answered: (i) to which extent is a ChIP-seq experiment able to reveal the weak ChIP-enriched sites? (ii) are the weak sites biologically meaningful? To answer these questions, it is necessary to identify the weak ChIP signals from background noise.
more » ... kground noise. Results: We propose a linear signal-noise model, in which a noise rate was introduced to represent the fraction of noise in a ChIP library. We developed an iterative algorithm to estimate the noise rate using a control library, and derived a library-swapping strategy for the false discovery rate estimation. These approaches were integrated in a general-purpose framework, named CCAT (Control-based ChIP-seq Analysis Tool), for the significance analysis of ChIP-seq. Applications to H3K4me3 and H3K36me3 datasets showed that CCAT predicted significantly more ChIP-enriched sites that the previous methods did. With the high sensitivity of CCAT prediction, we revealed distinct chromatin features associated to the strong and weak H3K4me3 sites.
doi:10.1093/bioinformatics/btq128 pmid:20371496 fatcat:5hps4poqdfc6fdbdvpesbm7ueu