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Figure 1. 

Summary of DNA methylation, histone modifications, and non-coding RNA in OA. (a) Dynamic changes of chromatin and the resultant gene expression in OA. Upper panel: regions of chromatin with activate transcription; lower panel: regions of chromatin with repressed transcription. (b) The epigenetic modulatory process of histone modifications, DNA methylation, and non-coding RNA; upper panel: histone modifications (histone modifications included methylation and acetylation); middle panel: DNA methylation (DNA methylation is dynamically maintaining the balance by adding methyl groups and deleting methyl groups in normal chondrocytes, and abnormal changes in DNA methylation occur in the promoter regions of related genes and signaling pathways in OA chondrocytes); lower panel: non-coding RNAs including lncRNA and miRNA modulate the gene expression during and post transcription. (c) Different classes of epigenetic enzymes responsible for the structural modification of chromosomes (DNA and histone) and its regulation effects. Ac: acetylation; DNMT: DNA methyltransferase; DOT1L: Disruptor of telomeric silencing 1-like; m: methylation; EZH: enhancer of zeste homolog; HDAC: histone deacetylase; KDM: histone lysine demethylase; NSD: H3K36 methyltransferase; Sirtuins: Sirt; TET: ten–eleven translocation enzyme.

Figure 2. 

Schematic diagram of RNA methylation in OA. OA is featured by cartilage degeneration, inflammatory synovium, periarticular bony changes (subchondral bone cyst, subchondral bone loss and sclerosis, osteophytes formation), accompanied by senescence of chondrocytes and cartilage debris. During OA progression, the function and fate of cells within the joint is regulated by N6-methyladenosine (m6A) methylation. The m6A mRNA 'life cycle': The m6A mRNA starts in the nucleus from in the nucleus during transcription. The m6A writer complex (box 1), which comprises the core methyltransferase-like protein 3 (METTL3) and its adaptors, is located in the nucleus, where it adds m6A co-transcriptionally. The m6A erasers are also largely localized in the nucleus. The main m6A eraser acting on m6A in mRNAs is ALKBH5. Fat mass and obesity-associated protein (FTO) has recently been found to preferentially target m6Am, not m6A, with its major target being m6Am in small nuclear RNAs (snRNAs). While in the nucleus, m6A can bind specific nuclear reader proteins, mainly YTHDC1 (DC1), which may affect splicing or other nuclear processes such as mRNA export. Upon mRNA export to the cytoplasm, m6A binds to specific reader proteins that affect the stability, translation and/or localization of the mRNA. In the cytoplasm, the m6A readers YTHDF1 (DF1), YTHDF3 (DF3), the eukaryotic translation initiation factor eIF3, and METTL3 all favour the translation of m6A mRNAs. YTHDF2 (DF2) and DF3 mediate the degradation of m6A mRNAs, while the insulin- like growth factor 2 mRNA-binding proteins (IGF2BP1/2/3), and the synaptic regulator FMRP (a polyribosome-associated RNA-binding protein known to have a central role in neuronal development and synaptic plasticity) enhance m6A mRNA stability. Am, methylated A; m6Am, N6, 2′-O- dimethyladenosine.

Figure 3. 

Overview of current multi-omics techniques in OA epigenetic research. An overview of the advanced multi-omics techniques used in OA research. Cleavage under targets and tagmentation: CUT Tag; Assay for Transposase Accessible Chromatin: ATAC; Chromatin Immunoprecipitation: ChIP.