Chromatin immunoprecipitation (ChIP) is an indispensable tool in the fields of 
epigenetics and gene regulation that isolates specific protein-DNA interactions. 
ChIP coupled to high throughput sequencing (ChIP-seq) is commonly used to 
determine the genomic location of proteins that interact with chromatin. 
However, ChIP-seq is hampered by relatively low mapping resolution of several 
hundred base pairs and high background signal. The ChIP-exo method is a refined 
version of ChIP-seq that substantially improves upon both resolution and noise. 
The key distinction of the ChIP-exo methodology is the incorporation of lambda 
exonuclease digestion in the library preparation workflow to effectively 
footprint the left and right 5' DNA borders of the protein-DNA crosslink site. 
The ChIP-exo libraries are then subjected to high throughput sequencing. The 
resulting data can be leveraged to provide unique and ultra-high resolution 
insights into the functional organization of the genome. Here, we describe the 
ChIP-exo method that we have optimized and streamlined for mammalian systems and 
next-generation sequencing-by-synthesis platform.