Repetitive elements, which comprise more than 55% of the human genome, consist mainly of retrotransposons and are the primary targets of DNA methylation. DNA methylation is also associated with increased levels of C-to-T mutations. However, DNA methylation in the gene bodies shows complicated correlations with transcription: most low and highly-expressed genes exhibit low levels of methylation in the gene bodies, whereas moderately expressed genes show the highest levels of methylation. Alternatively, 5mC attracts methyl-CpG-binding domain (MBD) proteins to attach to promoter regions, consequently blocking TF binding to regulatory elements. The repressive role of 5mC at gene promoters can be caused by directly preventing transcription factors (TFs) from binding to the corresponding elements, thereby blocking gene transcription. Promoter hypermethylation is often associated with gene silencing and has been frequently observed in cancer. ĭNA methylation plays a critical role at the molecular, biological, and pathological levels. Remarkably, gene regulatory elements, including enhancers and transcription-factor binding sites, exhibit dynamic DNA methylation across tissues and cell types. Like CGIs, most CpG-rich regions show low levels of methylation, whereas CpG-poor regions are generally hypermethylated in mammals. CGIs are typically 300-3,000 bp in length and overlap with 60% of human gene promoters and almost 100% of housekeeping gene promoters. The CpG-rich regions, where the C+G content exceeds 50% and the observed to expected CpG ratio is equal to or greater than 0.6, are called CpG islands (CGIs). CpGs are not randomly distributed across the genome, but exhibit widely scattered and locally clustered distributions. It occurs almost exclusively in the form of 5'-3' cytosine-phosphate-guanine (CpG) dinucleotides, and approximately 70-80% of CpGs are methylated in mammals. The 5-methylcytosine (5mC) is the dominant type of DNA modification, accounting for approximately 1% of the human genome. Another type of DNA methylation in mammals occurs at the N-6 position of adenine, although its functions are still under extensive investigation. DNA methylation is the most stable epigenetic modification. Keywords: DNA methylation, single-cell sequencing, single-cell multi-omics sequencing IntroductionĭNA methylation refers to the phenomenon in which a methyl group (CH3) from S-adenosylmethionine is transferred to the C-5 position of cytosine by DNA methyltransferases (DNMTs). Here, we summaries single-cell DNA methylation and multi-omics sequencing methods, delineate their applications in biomedical sciences, discuss technical challenges, and present our perspective on future research directions. Excitingly, many single-cell DNA methylation sequencing and single-cell omics sequencing technologies have been developed, and applications of these methods have greatly expanded our understanding of the molecular mechanism of DNA methylation. It is therefore essential to develop sequencing technologies that can accurately profile DNA methylation using small numbers of cells or even single cells. ![]() ![]() It is often not realistic to collect sufficient numbers of cells, such as rare cells and circulating tumor cells in peripheral blood, for bulk sequencing assays. Notably, conventional DNA methylation profiling technologies require a large amount of DNA, often from a heterogeneous cell population, and provide an average methylation level of many cells. Aberrant DNA methylation has been observed in human diseases, particularly cancer. DNA methylation is essential for many physiological and pathological processes. In mammals, it usually occurs at the cytosine of CpG dinucleotides. File import instruction AbstractĭNA methylation is the most stable epigenetic modification. Select the file that you have just downloaded and select import option Reference Manager (RIS). ![]() Technologies and applications of single-cell DNA methylation sequencing.
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