mChIP-seq for high-throughput epigenomic profiling reveals a decoupling of H2A.Z and H3K4me3 in cancer

Histone variant H2A.Z has multiple roles in regulating gene transcription and its overexpression has been observed in various cancer types. However, the epigenomic characterization of H2A.Z in cancer is unclear. Combining the pool-and-split strategy with sequencing, we developed mChIP-seq, a multiplexed chromatin immunoprecipitation followed by sequencing method to efficiently profile multifactorial epigenetic landscapes of histone marks for multiple samples in parallel. mChIP-seq generates high-quality profiles comparable to standard ChIP-seq but with merits of high efficiency, low cost, and low-input requirement. Using mChIP-seq to profile H2A.Z and 10 H3 histone modifications for 24 cancer cell lines spanning 9 cancer types, we generated 528 epigenomic profiles from two workflows, comprehensively characterized genomic distribution of H2A.Z, and revealed its associations with main histone modifications and gene expression. Moreover, compared with normal cells by integration analysis of public data, we found a decoupling of H2A.Z and H3K4me3 at promoter sites in cancer cells, where the signal intensity of H2A.Z is not in line with the signal intensity of H3K4me3, which further dysregulates gene expression. Altogether, our results demonstrate that mChIP-seq is a powerful technology for epigenomic profiling and reveal abnormal regulatory features of H2A.Z in cancer.