Epigenetics: Role of histone proteases in cellular functions and diseases

Abstract

In the past few decades, exciting advances have been made to understand the epigenetic regulation of chromatin structure and function. There has been tremendous progress in the identification and study of protein complexes of catalytic nature, which reversibly modify chromatin (DNA as well as histone proteins) during various nuclear processes that involves DNA. Histone proteins undergo post-translational modifications (PTMs) like acetylation, phosphorylation, ubiquitination, methylation, and proteolytic clipping. However, the proteolytic clipping of histone tails is not as well understood as other covalent modifications. In some cases, the proteolytic processing, particularly of histone H3 and H1, has been considered as a physiologically regulated event. For example, in Tetrahymena, six amino acids are removed from the NH 2 -terminus of histone H3 in transcriptionally silent micronuclei. Similarly, during viral infection of foot-and-mouth disease virus, H3 has been reported to be cleaved between Leu20 and Ala21 from the NH 2 -terminus. Lately, in parallel to the emergence of the histone code hypothesis, there has been substantial excitement in the field of site-specific proteolytic processing of some of the core histones. A chromatin-bound proteolytic activity with unique specificity for histone H2A has long been identified and characterized in quite detail. Recently, human Cathepsin L and an unidentified protease in yeast and another in chicken liver have been shown to cleave H3 from NH 2 -terminus. Such processing of histones has the potential to regulate chromatin dynamics to an extent that makes it physiologically relevant and crucial. This comprehensive review will shed light on advancements made so far on proteolytic processing of histones and future directions of study. Here we discuss the biochemical properties and biological functions of histone proteolysis in transcription, viral diseases, stem cell differentiation, and sporulation.