PT - JOURNAL ARTICLE AU - Antonio Lentini AU - Cathrine Lagerwall AU - Svante Vikingsson AU - Heidi K. Mjoseng AU - Karolos Douvlataniotis AU - Hartmut Vogt AU - Henrik Green AU - Richard R. Meehan AU - Mikael Benson AU - Colm E. Nestor TI - A reassessment of DNA immunoprecipitation-based genomic profiling AID - 10.1101/224279 DP - 2017 Jan 01 TA - bioRxiv PG - 224279 4099 - http://biorxiv.org/content/early/2017/11/24/224279.short 4100 - http://biorxiv.org/content/early/2017/11/24/224279.full AB - DNA immunoprecipitation sequencing (DIP-seq) is a common enrichment method for profiling DNA modifications in mammalian genomes. However, DIP-seq profiles often exhibit significant variation between independent studies of the same genome and from profiles obtained by alternative methods. Here we show that these differences are primarily due to intrinsic affinity of IgG for short unmodified DNA repeats. This pervasive experimental error accounts for 50 – 99% of regions identified as ‘enriched’ for DNA modifications in DIP-seq data. Correction of this error profoundly alters DNA modification profiles for numerous cell types, including mouse embryonic stem cells, and subsequently reveals novel associations between DNA modifications, chromatin modifications and biological processes. We propose new methodological guidelines that minimize the impact of these errors on future DIP-seq experiments and allow new insights to be made from the wealth of existing DIP-seq data.