Regulation of expression and function of protein arginine methyltransferase 4 (PRMT4/CARM1) : implication in differentiation and disease

Abstract

Post-translational modifications of proteins in cell bestow them with the ability to display multifaceted functional modalities. Presence or absence of certain chemical moieties on specific residues of proteins, with due alteration in structural architecture, dictate functional behavior of proteins, such as protein-protein interaction, protein-DNA interaction etc. Biological systems have evolved to employ such a strategy effectively to bring complexity as well as dynamicity in regulation of cellular processes, which remain poised with intricate balance among context dependent differential behaviors of thousands of biomolecules in cell. The N-terminal tail domains of core histones (H2A, H2B, H3, and H4) which protrude out of the nucleosomal structure of chromatin, have been shown to be primary sites for enzymatic modifications such as acetylation, phosphorylation, methylation, ubiquitylation, ADP ribosylation, crotonylation and sumoylation etc. (Fig. 1.1). With immediate effect on chromatin compaction dynamics these modifications play far more important role by acting as docking modules for differential recruitment of various proteins to regulate chromatin templated phenomena such as DNA replication, transcription, DNA repair etc. [Suganuma T et al., 2011]. For example, histone acetylation and phsophorylation are believed to achieve decondensation of chromatin via neutralization of positive charge and addition of negative charge to basic histones respectively. Considering the fact that open chromatin serves as a better template for transcriptional events; decondensation in general is considered to be a prerequisite for initiation and maintenance of transcription. Thus, experimental evidences more often link histone acetylation and phsoporylation to transcriptional activation in cell, although with a few exceptions. Conversely, histone deacetylases (HDACs) which remove acetyl groups from histones are known to associate with transcriptionally inactive chromatin.