Epigenetic Factors as Regulators of Gene Expression
The term 'epigenetics' was originally associated with heritable changes in gene activity that occur without alterations of the genetic code. Nowadays, the term is more often used to describe chromatin-related regulatory mechanisms that do not involve changes in the nucleotide sequence, regardless of whether such imprinting is strictly heritable. Posttranslational histone modifications such as acetylation, methylation or phosphorylation marks among others are added to histone side chains or to cytosine residues in the DNA (DNA methylation) by epigenetic 'writer' proteins (Fig. 1). These epigenetic marks are recognized by 'reader' proteins that serve as platforms and docking sites for effector proteins mediating fundamental processes such as transcription, DNA replication and recombination, DNA damage response and chromatin remodeling. Epigenetic 'eraser' proteins are capable of removing epigenetic marks. Understanding the intricate spatial and temporal interplay between different epigenetic modifications is one of the most challenging aspects in chromatin biology and at the beginning of exploration.
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Figure 1.
Epigenetic writer, reader and eraser proteins. Posttranslational histone modifications such as acetylation, methylation or phosphorylation marks are added to histone side chains by writer proteins and are recognized and get bound by reader proteins. Epigenetic reader proteins serve as a platform and docking site for effector proteins. Posttranslational histone modifications are removed by eraser proteins.
In addition to posttranslational histone modifications and DNA methylation, noncoding RNAs are additional factors that influence gene expression levels. Apart from microRNAs, which are small noncoding RNAs acting as destabilizers and repressors of translation, the functional role of other noncoding RNAs in RA has not been investigated yet. Long noncoding RNAs with a length of at least 200 nucleotides regulate gene expression levels by affecting the stability of mRNA, altering the translation efficiency, and functioning as precursors for mRNAs. Furthermore, long noncoding RNAs are capable of controlling the epigenetic state of particular genes by guiding chromatin-modifying complexes and other nuclear proteins to specific genomic loci to exert their effects. Song et al. have recently shown an altered pattern of long noncoding RNAs in peripheral blood mononuclear cells (PBMC) of RA patients compared with healthy controls but their impact on disease pathogenesis is at the beginning of investigation.