DNA Methylation and Differentiation: Silencing, Upregulation and Modulation of Gene Expression

Abstract

Differentiation-related DNA methylation is receiving increasing attention, partly owing to new, whole-genome analyses. These revealed that cell type-specific differential methylation in gene bodies is more frequent than in promoters. We review new insights into the functionality of DNA methylation during differentiation, with emphasis on the methylomes of myoblasts, myotubes and skeletal muscle versus non-muscle samples. Biostatistical analyses of data from reduced representation bisulfite sequencing are discussed. Lastly, a model is presented for how promoter and intragenic DNA hypermethylation affect gene expression, including increasing the efficiency of polycomb silencing at some promoters, downmodulating other promoters rather than silencing them, counteracting enhancers with heterologous specificity, altering chromatin conformation by inhibiting the binding of CTCF, modulating mRNA transcript levels by inhibiting overlapping promoters of noncoding RNA genes or by regulating the use of alternative mRNA promoters, modulating transcription termination, regulating alternative splicing and acting as barriers to the spread of activating chromatin.

Methylation of the oxytocin receptor gene in clinically depressed patients compared to controls: The role of OXTR rs53576 genotype

“…Today it is known that DNA methylation can also occur outside of CpG islands and throughout the genome, and that intronic CpG methylation or CpG methylation at CpG island shores are also of functional relevance. The former view that DNA methylation within the promoter region leads to gene silencing, has also been challenged recently, as more and more reports also show a positive relation between methylation and expression (Ehrlich and Lacey, 2013). Lately, the interaction between genotypes and DNA methylation has also found increased attendance, as some genotypes can affect DNA methylation throughout the whole genome (Chen et al, 2015).…”

Aberrant Epigenetic Regulation in the Pathogenesis of Systemic Lupus Erythematosus and Its Implication in Precision Medicine

“…For example, as mentioned above, DNA methylation is mainly established and maintained by DNMTs. It is also modified by methylCpG-binding domain proteins through recruiting silencing complexes containing HDACs and histone methyltransferases to participate in transcriptional repression [Ehrlich and Lacey, 2013]. DNA methylation and histone acetylation in CD4 + T cells of SLE patients are regulated by RFX1 by recruiting DNMT1 and HDAC1 to the CD11A (ITGAL) and CD70 promoters, and thereby their expression is repressed [Zhao et al, 2010a].…”

Epigenetics in autoimmune diseases: Pathogenesis and prospects for therapy

“…DNA methylation, a dynamic process involving methylation and demethylation events, occurs in different regions of the genome and is crucially important for embryogenesis, cellular proliferation and differentiation [11,12]. Methylation is established and maintained by the DNA methyltransferase (DNMT) family which is composed of a group of enzymes, including DNMT1, DNMT3a, DNMT3b, and DNMT3L.…”

“…7 nucleosome remodeling [12]. Meanwhile, cross-talks among various ncRNAs or between ncRNAs and other epigenetic mechanisms exist extensively as well [77].…”