Evolutionary conserved histone proteins play a very important role in the regulation of eukaryotic gene expression by undergoing post translational modifications within the tail regions. However, their role in tissue-specific gene expression and development remains unclear. In this study, we provide evidence for in vivo tissue-specific proteolytic cleavage of histone H3 in the liver of adult white Leghorn chickens, which we believe to be regulated by tissue-specific protease activity and epigenetic markers. The cleavage of histone H3 in the liver of adult chickens is very unique, and can serve as a model for studying tissue-specific changes in chromatin organization and gene expression. For the first time, we have identified and partially purified histone H3-specific protease activity that is distinct from histone H3 protease activities recently reported. Together, our data provide evidence of proteolytic processing and identification of protease activity that is specific to histone H3 in the liver of adult chickens, which may be involved in the regulation of gene expression during development, aging, and age-associated diseases. (C) 2012 Elsevier Inc. All rights reserved.