Enzymatic methods for genome-wide profiling of protein binding sites

Genome-wide mapping of protein-DNA interactions is a staple approach in many areas of modern molecular biology. Genome-wide profiles of protein-binding sites are most commonly generated by chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq). Although ChIP-seq has played a central role in studying genome-wide protein binding, recent work has highlighted systematic biases in the technique that warrant technical and interpretive caution and underscore the need for orthogonal techniques to both confirm the results of ChIP-seq studies and uncover new insights not accessible to ChIP. Several such techniques, based on genetic or immunological targeting of enzymatic activity to specific genomic loci, have been developed. Here, we review the development, applications and future prospects of these methods as complements to ChIP-based approaches and as powerful techniques in their own right.