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. 2020 Jan 17;128(1):015001. doi: 10.1289/EHP6104

Figure 1.

Figure 1A is a diagram representing DNA methylation and its relationship with repressive and active chromatin states. Pol II is included in the diagram in close proximity to the illustration of active chromatin. A curved arrow across the top of the figure represents the addition of methyl groups (Me) by DNMT enzymes, and a curved arrow in the opposite direction across the bottom of the figure represents the removal of methyl groups by TET enzymes. Figure 1B is a diagram illustrating the deposition of active and repressive histone marks and their effect on histone states (repressed, bivalent or active). A double-headed arrow illustrates the conversion between active and repressive histone marks by the enzymes HDACs, KDMs, HATs, and HMTs. A diagram of a hypothetical gene illustrates examples of active and repressive histone marks that can occur on the enhancer (e.g. H3K4me1 and H3K27ac active marks; H3K27me3 repressive mark), promoter (e.g. H3K4me3 active mark, H3K27me3 repressive mark), and gene body (e.g. H3K36me3 active mark, H3K9me3 repressive mark). Figure 1C is a diagram illustrating the modes of action of microRNAs, which interact with AGO proteins to trigger the inhibition of the eIF4F complex (left), mRNA cleavage (middle), and mRNA deadenylation followed by degradation by XRN1 (right). Figure 1D is a diagram illustrating the modes of action of lncRNAs, namely mRNA stabilization; miRNA or TF sequestration; TF recruitment or inhibition (with TFs represented by an ellipse or rectangle); and chromatin remodeling by recruitment of chromatin remodeling factors (CRFs).

Diagrammatical summary of epigenetic modes on action. (A) The deposition of methyl groups is mediated by the DNA methyltransferases (DNMTs), and their removal is mediated by the ten-eleven translocation (TET) family proteins (reviewed by Greenberg and Bourc’his 2019; Wu and Zhang 2010). Increased deposition of methyl groups promotes the condensation of chromatin, whereas reduced DNA methylation is associated with increased accessibility to transcription machinery [represented by RNA polymerase II (Pol II)]. DNA hypermethylation generally leads to the silencing of gene expression when it occurs at gene promoters (reviewed by Greenberg and Bourc’his 2019; Wu and Zhang 2010). (B) Histone modifications are deposited by multiple classes of enzymes [histone acetyltransferases (HATs), histone methyltransferases (HMTs), histone deacetylases (HDACs), and histone lysine demethylases (KDMs)] (reviewed by Chen et al. 2017). Examples of histone modifications illustrated here are histone H3 lysine 27 trimethylation (H3K27me3) and H3 lysine 9 trimethylation (H3K9me3), which are usually associated with repression of gene transcription, and H3 lysine 4 monomethylation (H3K4me1), H3 lysine 4 trimethylation (H3K4me3), H3 lysine 36 trimethylation (H3K36me3), and H3 lysine 27 acetylation (H3K27ac) marks that are typically associated with activation of transcription. Simultaneous deposition of opposing histone marks is associated with poised or bivalent chromatin, which is in a transitional state poised to be resolved into active or repressed states (reviewed by Chen et al. 2017). (C) microRNAs (miRNAs) bound to the Argonaute (AGO) protein make up the miRNA-induced silencing complex (miRISC). miRNAs direct the miRISC to target mRNAs base-pairing partially to complementary binding sites, which will be cleaved by catalytically active AGO proteins (O’Brien et al. 2018). Alternatively, AGO proteins can recruit additional protein partners, initiating the process of deadenylation, decapping and 5ʹ-to-3ʹ mRNA degradation by 5ʹ-to-3ʹ exoribonuclease 1 (XRN1) (reviewed by Jonas and Izaurralde 2015). There has also been evidence that miRNAs inhibit translation by inhibiting the eukaryotic initiation factor 4F (eIF4F) complex, although this process has yet to be fully elucidated (reviewed by Jonas and Izaurralde 2015). 5ʹ polyA tails are denoted by circles labeled A. (D) Long noncoding RNAs (lncRNAs) may influence gene expression by increasing or decreasing target mRNA stability, by acting as decoys to miRNA and transcription factors (TFs), thus sequestering them from their cognate promoters, or they may recruit or inhibit TF binding to their target sites on the chromatin (reviewed by Angrand et al. 2015). lncRNAs may also recruit chromatin remodeling factors (CRFs) such as the polycomb repressive complexes or cohesin proteins that recruit histone modifier complexes or initiate long-range chromatin looping (reviewed by Angrand et al. 2015). The Xist lncRNA triggers stable repression of the presumptive inactive X-chromosome by physically coating the X-chromosome (reviewed by Lee and Bartolomei 2013).