Chromatin immunoprecipitation (ChIP) is becoming the standard method to study genome-wide distribution of histone variants and histone posttranslational modifications (PTMs). In this chapter, we describe a detailed native ChIP protocol and downstream procedures for the preparation of DNA libraries for next-generation sequencing. Compared to cross-linked ChIP, "native" ChIP has been shown to produce occupancy pattern data of histone PTMs and histone variants, with higher resolution and higher signal to noise ratio. We further present an adaptation of this protocol to perform native ChIP from as low as 50,000 cells.
