Rapid profiling of transcription factor–cofactor interaction networks reveals principles of epigenetic regulation

Abstract

Abstract Transcription factor (TF)–cofactor (COF) interactions define dynamic, cell-specific networks that govern gene expression; however, these networks are understudied due to a lack of methods for high-throughput profiling of DNA-bound TF–COF complexes. Here, we describe the Cofactor Recruitment (CoRec) method for rapid profiling of cell-specific TF–COF complexes. We define a lysine acetyltransferase (KAT)–TF network in resting and stimulated T cells. We find promiscuous recruitment of KATs for many TFs and that 35% of KAT–TF interactions are condition specific. KAT–TF interactions identify NF-κB as a primary regulator of acutely induced histone 3 lysine 27 acetylation (H3K27ac). Finally, we find that heterotypic clustering of CBP/P300-recruiting TFs is a strong predictor of total promoter H3K27ac. Our data support clustering of TF sites that broadly recruit KATs as a mechanism for widespread co-occurring histone acetylation marks. CoRec can be readily applied to different cell systems and provides a powerful approach to define TF–COF networks impacting chromatin state and gene regulation.