The proteolytic cleavage of histone tails, also termed histone clipping, has been described as a mechanism for permanent removal of post-translational modifications (PTMs) from histone proteins. Such activity has been ascribed to ensure regulatory function in key cellular processes such as differentiation, senescence and transcriptional control for which different histone-specific proteases has been described. However, all these studies were exclusively performed using cell lines cultured in vitro and no clear evidences that histone clipping is regulated in vivo has been reported. Here we show that histone H3 N-terminal tails undergo extensive cleavage in the differentiated cells of the villi fraction of the mouse intestinal epithelium and we investigate histone PTM changes in full-length compared with clipped histone H3.