MEFs were first cross-linked with 1% formaldehyde for 20 mins, and then lysed with the buffer containing protease inhibitor cocktail (Millipore, Cat. No. 539131). The released nuclei were fractionated with sonication to a pool of DNA fragments size-ranging from 300 to 1,000 bp in length. The prepared chromatin was immunoprecipitated with the H4K16ac antibody. The two pools of the immunoprecipitated DNA along with the two corresponding input DNA were used for constructing libraries for ChIP-seq experiments according to the manufacturers’ protocol (Illumina FC4014003).