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Circulating cell-free, methylated DNA reveals tissue-specific, cellular damage from radiation treatment [Mouse Serum MCC-seq]

ABSTRACT: Radiation therapy is an effective cancer treatment although damage to healthy tissues is common. Here we establish sequencing-based, cell-type specific DNA methylation reference maps of human and mouse tissues to infer the origins of cell-free DNA fragments released from dying cells into the circulation. We find cell-type specific DNA blocks mostly hypomethylated and located within genes intrinsic to cellular identity. In a mouse model, thoracic radiation-induced tissue damages were reflected by dose-dependent increases in lung endothelial, cardiomyocyte and hepatocyte methylated DNA in serum. The analysis of serum samples from breast cancer patients undergoing radiation treatment revealed distinct tissue-specific epithelial and endothelial responses to radiation across multiple organs. Strikingly, patients treated for right-sided breast cancers also showed increased hepatocyte and liver endothelial DNA in the circulation indicating the impact on liver tissues. Thus, cell-free methylated DNA in serum can uncover cell-type specific effects of radiation on healthy tissues and inform treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE200094 | GEO | 2023/07/24

REPOSITORIES: GEO

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Project description:Purpose: Aberrantly methylated DNA are hallmarks for many cancers, HCC included. Tumor shed its DNA into circulation stream, and serum DNA methylation analysis is a less-invasive and accessable way to judge the primary tumor status. The goals of this study are to compare DNA methylation profiling in serum cell-free DNA from different stages of HCC progression including healthy control, chronic HBV carrier, HBV-related liver Cirrhosis and HCC, to establish HCC development-related aberrnat DNA methylation patterns. Methods: MBD methylCap/seq was carried out to screen differentially methylated CpG islands in serum cell-free DNA on four different stage of HBV-related HCC development. MSP and multiplex-BSP validation was performed using independent serum DNA or tumor and adjacent tissues. Results: Using a MBD methylCap/seq platform, we produced 33- to 37- million raw reads per sample and mapped them, in about half of the raw reads, to human genome(build h19) in the serum cf DNA of healthy control, HBV carrier, HBV cirrhosis and HCC. The mapped reads formed 180k to 260k peaks per sample, with 160 k common peaks shared by four samples. After subtraction of the common peaks, there left 51k, 107k and 78 k DMRs representing hypermethylations, in HBV carrier, HBV cirrhosis and HCC, respectively. We define those DMRs as early, middle and late when these DMRS occurred and maintained in HBV carrier, HBV cirrhosis and HCC, which including 27k, 24k and 19k DMRs, corresponding to 1,416, 1,337, 1,006 genes. GO analysis of them revealed gene categories and pathways associated with tumorogenenisis related process Conclusions: Our study represents the first detailed analysis of serum cf-DNA methylation profiling in the progression of HBV related HCC development. The processed data analysis here offers a comprehensive evaluation of DNA methylation in serum cf DNA. We conclude that MBD methylCap/seq based methylation profiling would benefit epigenetic research in HCC.

Project description:<p>Aberrant DNA methylation changes are known to occur during prostate cancer progression beginning with precursor lesions. Utilizing fifty nanograms of genomic DNA in Methylplex-Next Generation Sequencing (M-NGS) we mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2). Peaks were located from mapped reads obtained in each sequencing run using a Hidden Markov Model (HMM)-based algorithm previously used for Chip-Seq data analysis(<a href="http://www.sph.umich.edu/csg/qin/HPeak">http://www.sph.umich.edu/csg/qin/HPeak</a>). The total methylation events in intergenic/intronic regions between benign adjacent and cancer tissues were comparable. Promoter CGI methylation gradually increased from -12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues and approximately 20% of all CpG islands (CGIs) (68,508) were methylated in tissues. We observed distinct patterns in promoter methylation around transcription start sites, where methylation occurred directly on the CGIs, flanking regions and on CGI sparse promoters. Among the 6,691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer specific and several previously studied targets were among them. A novel cancer specific DMR in WFDC2 promoter showed 77% methylation in cancer (17/22), 100% methylation in transformed prostate cell lines (6/6), none in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested a role for DNA methylation in alternate transcription start site utilization. While methylated promoters containing CGIs had mutually exclusive H3K4me3 modification, the histone mark was absent in CGI sparse promoters. Finally, we observed difference in methylation of LINE-1 elements between transcription factor ERG positive and negative cancers. The comprehensive methylome map presented here will further our understanding of epigenetic regulation of the prostate cancer genome. Overall Design: We mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2) from fifty nanograms of genomic DNA using Methylplex-Next Generation Sequencing (M-NGS). For replicate analysis in cell lines, a total of 4 runs were completed for PrEC prostate normal cell line, and 5 runs were completed for LNCaP prostate cancer cell line. For tissue samples, 2 benign prostate samples were sequenced twice on Illumina next generation sequencing platform to access overall repeatability of M-NGS.</p>

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Circulating cell-free, methylated DNA reveals tissue-specific, cellular damage from radiation treatment [Mouse Serum MCC-seq]

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