The role of VRK1 in chromatin remodeling: regulation of histone post-translational modifications and epigenetic enzymes

Abstract

DNA organization is essential for proper chromatin packaging and necessary to facilitate different processes that require dynamic chromatin remodeling. Modulation of chromatin structure is critical for the regulation of gene expression, since it determines which genes are accessible for transcription and the sequential recruitment of regulatory factors to the underlying DNA. Thus, to deal with inaccessible chromatin, eukaryotic cells have developed mechanisms that facilitate the opening of chromatin. Epigenetic alterations are defined as mechanisms that control DNA accessibility for the regulation of gene expression patterns and normal development. The epigenetic transcriptional control can occur through DNA methylation, histone post-translational modifications (PTMs), the reading of these modifications by epigenetic enzymes, histone-variants exchange, and noncoding RNA. Errors in the epigenetic regulation can alter the control of chromatin-based processes, ultimately leading to abnormal gene expression. Pathological conditions such as cancers, metabolic disorders, and inflammatory and neurodegenerative diseases have been found to be related to epigenetic errors. Post-translational modifications (PTMs) of the N-terminal tail of histones regulate DNA access. Importantly, histone PTMs are reversible, and their coordination requires a tight regulation of multiple epigenetic enzymes, known as writers (enzymes that add a mark) and erasers (enzymes that remove a mark) 111 . Among the different PTMs, acetylation and methylation are especially important. They have been extensively investigated in a context of cancer and therapy responses. The balance between de-and acetylation is controlled by deacetylases (HDACs) and acetyltransferases (HATs), while de-and methylation are regulated by demethylases (KDMs) and methyltransferases (KMTs).