TIP-ChIP: Tagmented, indexed and pooled ChIP-seq to generate high-throughput, multi-sample results for low input samples

Epigenetic profiling approaches have greatly expanded our understanding of the mechanisms underlying gene regulation and disease. Histone modifications and transcription factors play a crucial role in chromatin organization and transcriptional control, with dysregulation often linked to various pathological conditions. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) remains the gold standard for genome-wide mapping of histone modifications; however, its high input requirements, susceptibility to batch effects, and labor-intensive workflow limit its scalability and efficiency. Here we present Tagmented, Indexed and Pooled ChIP (TIP-ChIP), a high-throughput alternative that enables the simultaneous profiling of histone modifications and transcription factors across up to 96 samples in a single reaction. This method substantially reduces batch effects, enhances reproducibility, and requires significantly lower input material compared to conventional ChIP-seq. Furthermore, the streamlined workflow can be completed in as little as 3 days, minimizing hands-on time and reducing overall costs while maintaining high sensitivity and resolution. By leveraging an optimized plate-based workflow and a tagmentation barcoding strategy that enables pooling, our method allows for efficient sample multiplexing without compromising data quality. To validate its performance, we apply this approach across multiple cell types, including human primary cells, and demonstrate strong concordance with conventional ChIP-seq for both histone modifications and transcription-factor targets. Further, TIP-ChIP captured dynamic chromatin and transcriptional responses in LPS-stimulated THP-1 cells, revealing time-resolved changes in H3K27ac, H3K4me3, RNA polymerase II Ser2P, and NF-κB (p50). This advancement makes large-scale epigenomic and TF-profiling studies more accessible and cost-effective, enabling the investigation of regulatory dynamics across diverse biological contexts with unprecedented efficiency