ABSTRACT
JIGNESHKUMAR PATEL, RAVI R. PATHAK, and SHIRAZ MUJTABA
INTRODUCTION
DNA methylation and lysine modifications comprise major epigenetic processes on chromatin, which alter nucleosomal architecture leading to gene activation or repression [1-3]. Dynamic post-translational modifications (PTMs) occurring in the proximity of a gene promoter are one of the hallmarks of epigenetic regulation of gene expression [4]. Although an individual lysine residue may undergo mutually exclusive multiple PTMs, including acetylation, methylation, neddylation, ubiquitination and sumoylation, multiple lysines of a single protein can undergo diverse modifications [5,6]. Functionally, these site-specific PTMs, which are established during transcriptional programming, impart flexibility to regulate cellular processes in response to diverse physiological and external stimuli. PTMs impact functional capabilities of a protein, thus validating the notion that biological complexities are not restricted only by the number of genes [7]. To elucidate the functional consequences of a single PTM or combinatorial PTMs occurring on chromatin, the histone code hypothesis proposes to integrate the gene regulatory ability of a site-specific histone modification within its biological context [8,9]. In quintessence, a site-specific PTM serves as a mark to recruit a chromatin-associated protein complex(es) that participates in controlling gene activity, thereby, regulating cell fate decisions [10]. For instance, within chromatin, depending on the site and degree of the modification, lysine methylation can cause either gene activation or repression; lysine acetylation on histones
is associated with chromatin relaxation contributing to gene activation; and the biochemical outcome of lysine ubiquitination or sumoylation is dynamic turnover of proteins. In addition, although the role of methylation in modulating non-histone proteins, including transcription factor activity, is only beginning to be understood, acetylation of transcription factors can affect their DNA-binding ability, stability, nuclear translocation and capacity to activate target genes [7,11].
