Relationship between ultra-short DNA low methylation region and chromatin 3D structure
Last Update: 2021-03-02
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DNA methylation modification has always been a closely watched aesthetic genetic modification. As a gold standard for mapping DNA methylation spectrum, whole genome sulphate sequencing (WGBS) has the advantages of single base high resolution and whole genome high pass, so it is a frontier subject of oscic genetics research to fully analyze DNA methylation spectrum and excavate its regulatory function. The team, led by Professor Wei Li of Baylor College of Medicine in the United States, published a research paper in the journal
Biology. Through innovative calculation methods, this paper discovers a new oscic regulatory element related to chromatin 3D structure -- sparse conservative low methylation CpG (scUMC: Sparse conserved under-methylated CpGs), which provides a new research idea for ophthalmogenetic regulation.
DNA methylation plays an important regulatory role in a variety of biological processes, such as normal development and disease occurrence. High methylation CpG accounted for the majority (70-80%) of the entire DNA methylation group, and low methylation CpG clusters formed low methylation regions, usually concentrated in gene regulatory areas, and a number of low methylated DNA components have been found in the combined regions of promoter, enhancer and transcription factors. Previous DNA methylation analysis methods have generally found that the adjacent CpG methylation levels are also highly consistent. Therefore, in order to increase the credibility of the analysis, traditional methods often require that the low methylation area must include at least four low methylation CpG. In this process, a large number of sparsely distributed low methylated CpGs are discarded. In addition, although WGBS is a single base resolution, traditional methods do not predict methylation from a single base resolution. By developing novel calculation methods, this study detects the functional single base sparse conservative low methylation CpG (scUMC) and integrates the chromatin advanced structural data to analyze its potential regulatory functions in depth.
study found that the vast majority of single-base low-methylated CpGs were randomly distributed in each sample compared to previously detected low methylation CpG cluster areas. Therefore, the key to detect functional single-base low methylation CpG from a large amount of noise is to effectively distinguish and exclude randomly distributed single-base low methylation CpG. Based on another dimension, this study cleverly integrated the correlation of single-base low methylation CpG in multiple samples in high-quality WGBS data (31 sets of human normal cell line WGBS data) vertically, and developed a new calculation method to detect 9,421 functional single-base low-methylated CpG. Most of these single-base low-methylated CpGs are located in an open area of chromatin (DNase I hypersensitivity site), suggesting the function of these low-methylation site genes. Unlike traditional low-methylated CpG clustering regions, these mono-base low-methylated CpG sparse distributions are distributed in high methylated backgrounds, and their sequence and low methylation levels are conservative, so researchers call them sparse conservative low-methylated CpGs (scUMC: Sparseserved conserve-methylated CpGs). scUMC has unique characteristics that are different from previous low methylation clustering areas. scUMC is not in the CpG dense area and, accordingly, in and around CpG Island. Combined with the functional components defined by the ENCODE project and the ChIP-seq data of the 161 transcription factor, further analysis shows that scUMC is rich in the combined position of the transcription factor (distal TFBS) of non-starters and non-enhancers.
rich analysis of 161 transcription factors showed that scUMC was specifically associated with four chromatin ring factors (Rad21, SMC3, CTCF, ZNF143) and was correspondingly rich in DNA ring binding knots. DNA rings in the nucleosphere are the basic functional structures of cells, and their formation and conciliation allow cells to establish various advanced chromosome 3D structures and achieve gene regulation. Previous studies have shown that Radio21, SMC3, CTCF, ZNF143, these transcription factors are responsible for the 3D structure of tissue chromatin in the nucleus of the cell, and they come together to form binding nodes that trout genes from the far end to the promoter region, forming and maintaining ribbon-like DNA rings. ChIA-PET sequencing technology is able to identify DNA rings associated with specific transcription factors within the genome. In order to further study how scUMC participates in the formation of chromatin 3D structure, this study effectively uses existing public data to associate scUMC methylation levels with chromatin ring factors and DNA rings. The results showed that although the background around scUMC was high methylation, with the increase of individual base scUMC methylation, the chromatin ring factor binding DNA strength decreased, and the mutual effect of DNA ring binding knots decreased correspondingly; This study detects new oscic genetic components that regulate gene transcription and helps to open up a new direction of surface regulation research: individual CpG methylation-linked chromatin advanced structure regulates gene expression.
Wei Li, Professor of Bioinfoysy at Baylor College of Medicine. Dr. Li Wei has made many outstanding and original contributions to large-scale genomic data analysis over the years, and has worked with experimental biologists to complement each other and interpret many key issues of disease, especially in the course of tumor development, from a bio-informational perspective. Professor Li Wei, as project leader, has published more than 100 peer-reviewed papers in internationally renowned journals since 2008, including more than 30 in the Nature, Science and Cell magazine series. The total number of references to Dr. Li Wei's paper on Google Scholar has exceeded 22,000, with H-index at 53. Dr. Wei Li currently serves as a NATIONAL Health Fellow (NIH) and a PI and co-PI in several research projects of the Texas Cancer Foundation. Over the past five years, about $5 million in government research funds have been awarded to the lab. Five of the students in his lab have found positions as independent assistant professors at america's top research institutions.
First Lin Xueqiu, Ph.D., Tongji University, mentor Professor Li Wei. During his ph.D., he developed relevant computational tools and methods for DNA methylation and other surface modifications, mainly analyzing the role of surface genetic regulation in cell differentiation and tumor occurrence from big data. The findings were published in leading international journals such as Nature Genetics, Genome Biology, bioinformatics, and others. (Source: Science.com)
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