In order to evaluate cell-and disease-specific changes in the interacting strength of chromatin targets, ChIP-seq signal across multiple conditions must undergo robust normalization. However, this is not possible using the standard ChIP-seq scheme, which lacks a reference for the control of biological and experimental variabilities. While several studies have recently 20proposed different solutions to circumvent this problem, substantial technical and analytical differences among methodologies could hamper the experimental reproducibility and the quantitative accuracy. Here we propose a local regression strategy to accurately normalize ChIP-seq data in a genome-wide manner. Overall, our proposed experimental and computational standard for comparative ChIP-seq (Comp-ChIP-seq) will increase 25 experimental reproducibility, thereby reducing this major confounding factor in interpreting ChIP-seq results.
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