In the nuclei of eukaryotic cells, genomic DNA is packaged into chromatin, which is composed of DNA and proteins. The unit of chromatin is the nucleosome, which consists of an octamer of four core histone proteins (H2A, H2B, H3 and H4) that are wrapped around ~147 base pairs of DNA in 1.64 left-handed turns . There are 14 contact points between the histones and DNA per nucleosome . The striking feature of histones is their N-terminal ‘tails’, which are unstructured. A large number and different types of modified residues are placed on the tail of the histone. All of the histones are subjected to post-transcriptional modifications. There are at least eight distinct types of modifications, including lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, lysine ubiquitylation, lysine sumoylation, ADP ribosylation, arginine deimination and proline isomerization . In general, acetylation, methylation, phosphorylation, and ubiquitylation of histones have been implicated in the activation of transcription; whereas methylation, ubiquitination, sumoylation, deimination, and proline isomerization of histones have been implicated in the repression of transcription. Among these modifications, histone acetylation is most well studied. In mammalian cells, acetylation is directly performed by histone acetyltransferases (HATs) from acetyl-coenzyme A complexes. HATs are divided into three families, including GNAT, MYST and CBP/p300 [9, 39]. Histone tails are acetylated by HATs, resulting in the neutralization of their positive charge and the relaxation of the chromatin structure. This change in the chromatin structure increases the accessibility of transcription factors to their target genes. Spin et al. further demonstrated that p300 is involved in regulation of VSMC phenotypic switch and implicates the complex role of p300 in chromatin remodelling . In contrast, acetyl groups can be removed from histones by histone deacetylases (HDACs). There are three distinct families of HDACs: class I (HDAC1-3 and HDAC8), class II (HDAC4-7 and HDAC9-10) and class III [NAD-dependent enzymes of the sirtuin (SIRT) family (SIRT1-7)] . Class I HDACs are expressed ubiquitously in the nucleus and display high enzymatic activity. Class II HDACs are further subdivided into IIA and IIB. Class IIA HDACs (HDAC4-5, HDAC7 and HDAC9) have long N-terminal extensions with conserved binding sites for the transcription factor myocyte enhancer factor-2 (MEF-2) and the chaperone protein 14-3-3, which regulates nuclear-cytoplasmic shuttling . Class IIA HDACs can be phosphorylated by kinases, thereby providing a mechanism for linking extracellular signals with transcription. Class IIB HDAC6 is the primary cytoplasmic deacetylase found in mammalian cells, whereas the functions of HDAC10 are less known. Class III HDACs represent the silent information regulator 2 (Sir2) family of nicotinamide adenine dinucleotide (NAD+)-dependent HDACs (i.e. SIRT1-7), which share structural and functional similarities with yeast Sir2 . Histone acetylation is a dynamic process that is controlled by the antagonistic actions of two large families of enzymes . The balance between these actions represents a critical regulatory mechanism for gene expression, developmental processes and disease progression. Recently, HDACs and HDAC inhibitors have been suggested as clinical therapies for several diseases, such as cancer, cardiovascular diseases, Huntington's disease and Alzheimer's disease [43-45]. HDAC inhibitors will likely widen the therapeutic window and possibly lead to their clinical application .
In addition to histone modifications, chromatin remodelling can be achieved by ATP-dependent chromatin remodelling complexes . These chromatin remodelling complexes utilize ATP hydrolysis to alter the histone-DNA interaction. The consequences of chromatin remodelling lead to the transient unwrapping of the DNA from the histones, the formation of a DNA loop and the removal of the nucleosome and histone variants; each of these processes results in changes in the accessibility of nucleosomal DNA to transcription factors. These alterations in chromatin structure lead to changes in transcription in a wide variety of biological processes and provide a complex and responsive epigenetic landscape that is superimposed on the underlying genetic code.