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Quantification and mapping of DNA modifications.

ABSTRACT: Apart from the four canonical nucleobases, DNA molecules carry a number of natural modifications. Substantial evidence shows that DNA modifications can regulate diverse biological processes. Dynamic and reversible modifications of DNA are critical for cell differentiation and development. Dysregulation of DNA modifications is closely related to many human diseases. The research of DNA modifications is a rapidly expanding area and has been significantly stimulated by the innovations of analytical methods. With the recent advances in methods and techniques, a series of new DNA modifications have been discovered in the genomes of prokaryotes and eukaryotes. Deciphering the biological roles of DNA modifications depends on the sensitive detection, accurate quantification, and genome-wide mapping of modifications in genomic DNA. This review provides an overview of the recent advances in analytical methods and techniques for both the quantification and genome-wide mapping of natural DNA modifications. We discuss the principles, advantages, and limitations of these developed methods. It is anticipated that new methods and techniques will resolve the current challenges in this burgeoning research field and expedite the elucidation of the functions of DNA modifications.

SUBMITTER: Dai Y

PROVIDER: S-EPMC8341653 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Motivation5-methylcytosine (5mC) is a widely studied epigenetic modification of DNA. The ten-eleven translocation (TET) dioxygenases oxidize 5mC into oxidized methylcytosines (oxi-mCs): 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). DNA methylation modifications have multiple functions. For example, 5mC is shown to be associated with diseases and oxi-mC species are reported to have a role in active DNA demethylation through 5mC oxidation and DNA repair, among others, but the detailed mechanisms are poorly understood. Bisulphite sequencing and its various derivatives can be used to gain information about all methylation modifications at single nucleotide resolution. Analysis of bisulphite based sequencing data is complicated due to the convoluted read-outs and experiment-specific variation in biochemistry. Moreover, statistical analysis is often complicated by various confounding effects. How to analyse 5mC and oxi-mC data sets with arbitrary and complex experimental designs is an open and important problem.ResultsWe propose the first method to quantify oxi-mC species with arbitrary covariate structures from bisulphite based sequencing data. Our probabilistic modeling framework combines a previously proposed hierarchical generative model for oxi-mC-seq data and a general linear model component to account for confounding effects. We show that our method provides accurate methylation level estimates and accurate detection of differential methylation when compared with existing methods. Analysis of novel and published data gave insights into to the demethylation of the forkhead box P3 (Foxp3) locus during the induced T regulatory cell differentiation. We also demonstrate how our covariate model accurately predicts methylation levels of the Foxp3 locus. Collectively, LuxGLM method improves the analysis of DNA methylation modifications, particularly for oxi-mC species.Availability and implementationAn implementation of the proposed method is available under MIT license at https://github.org/tare/LuxGLM/ CONTACT: taijo@simonsfoundation.org or harri.lahdesmaki@aalto.fiSupplementary informationSupplementary data are available at Bioinformatics online.

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Quantification and mapping of DNA modifications.

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