DNA methylation and gene expression as determinants of genome-wide cell-free DNA fragmentation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Aug 2024
06 Aug 2024
Historique:
received:
24
07
2023
accepted:
23
07
2024
medline:
7
8
2024
pubmed:
7
8
2024
entrez:
6
8
2024
Statut:
epublish
Résumé
Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection.
Identifiants
pubmed: 39107309
doi: 10.1038/s41467-024-50850-8
pii: 10.1038/s41467-024-50850-8
doi:
Substances chimiques
Cell-Free Nucleic Acids
0
Isocitrate Dehydrogenase
EC 1.1.1.41
IDH1 protein, human
EC 1.1.1.42.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6690Informations de copyright
© 2024. The Author(s).
Références
Richmond, T. J., Finch, J. T., Rushton, B., Rhodes, D. & Klug, A. Structure of the nucleosome core particle at 7 Å resolution. Nature 311, 532–537 (1984).
doi: 10.1038/311532a0
Richmond, T. J. & Davey, C. A. The structure of DNA in the nucleosome core. Nature 423, 145–150 (2003).
doi: 10.1038/nature01595
Ceppellini, R., Polli, E. & Celada, F. A DNA-reacting factor in serum of a patient with lupus erythematosus diffusus. Proc. Soc. Exp. Biol. Med. 96, 572–574 (1957).
doi: 10.3181/00379727-96-23544
Miescher, P. & Strässle, R. New serological methods for the detection of the L. E. Factor. Vox Sang. 2, 283–287 (1957).
Seligmann, M. [Demonstration in the blood of patients with disseminated lupus erythematosus a substance determining a precipitation reaction with desoxyribonucleic acid]. Comptes Rendus Hebd. Des. Seances De. L’academie Des. Sci. 245, 243–245 (1957).
Robbins, W. C., Holman, H. R., Deicher, H. & Kunkel, H. G. Complement fixation with cell nuclei and DNA in lupus erythematosus. Proc. Soc. Exp. Biol. Med. 96, 575–579 (1957).
doi: 10.3181/00379727-96-23545
Barra, G. B. et al. EDTA-mediated inhibition of DNases protects circulating cell-free DNA from ex vivo degradation in blood samples. Clin. Biochem. 48, 976–981 (2015).
doi: 10.1016/j.clinbiochem.2015.02.014
Cristiano, S. et al. Genome-wide cell-free DNA fragmentation in patients with cancer. Nature 570, 385–389 (2019).
doi: 10.1038/s41586-019-1272-6
Snyder, M. W. et al. Comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell 164, 57–68 (2016).
doi: 10.1016/j.cell.2015.11.050
Foda, Z. H. et al. Detecting liver cancer using cell-free DNA fragmentomes. Cancer Discov. 13, 616–631 (2023).
doi: 10.1158/2159-8290.CD-22-0659
Moss, J. et al. Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease. Nat. Commun. 9, 5068 (2018).
doi: 10.1038/s41467-018-07466-6
Loyfer, N. et al. A DNA methylation atlas of normal human cell types. Nature 613, 355–364 (2023).
doi: 10.1038/s41586-022-05580-6
Fortin, J.-P. & Hansen, K. D. Reconstructing A/B compartments as revealed by Hi-C using long-range correlations in epigenetic data. Genome Biol. 16, 180 (2015).
doi: 10.1186/s13059-015-0741-y
Collings, C. K., Waddell, P. J. & Anderson, J. N. Effects of DNA methylation on nucleosome stability. Nucleic Acids Res. 41, 2918–2931 (2013).
doi: 10.1093/nar/gks893
Keshet, I., Yisraeli, J. & Cedar, H. Effect of regional DNA methylation on gene expression. Proc. Natl Acad. Sci. USA 82, 2560–2564 (1985).
doi: 10.1073/pnas.82.9.2560
Ulz, P. et al. Inferring expressed genes by whole-genome sequencing of plasma DNA. Nat. Genet. 48, 1273–1278 (2016).
doi: 10.1038/ng.3648
Esfahani, M. S. et al. Inferring gene expression from cell-free DNA fragmentation profiles. Nat. Biotechnol. 40, 585–597 (2022).
doi: 10.1038/s41587-022-01222-4
Zhou, Q. et al. Epigenetic analysis of cell-free DNA by fragmentomic profiling. Proc. Natl Acad. Sci. USA 119, e2209852119 (2022).
doi: 10.1073/pnas.2209852119
Chan, K. C. A. et al. Second generation noninvasive fetal genome analysis reveals de novo mutations, single-base parental inheritance, and preferred DNA ends. Proc. Natl Acad. Sci. USA 113, E8159–E8168 (2016).
doi: 10.1073/pnas.1615800113
Serpas, L. et al. Dnase1l3 deletion causes aberrations in length and end-motif frequencies in plasma DNA. Proc. Natl Acad. Sci. USA 116, 641–649 (2019).
doi: 10.1073/pnas.1815031116
Jin, C. et al. Characterization of fragment sizes, copy number aberrations and 4‐mer end motifs in cell‐free DNA of hepatocellular carcinoma for enhanced liquid biopsy‐based cancer detection. Mol. Oncol. 15, 2377–2389 (2021).
doi: 10.1002/1878-0261.13041
Trifonov, E. N. Cracking the chromatin code: precise rule of nucleosome positioning. Phys. Life Rev. 8, 39–50 (2011).
doi: 10.1016/j.plrev.2011.01.004
Norris, D. P., Brockdorff, N. & Rastan, S. Methylation status of CpG-rich islands on active and inactive mouse X chromosomes. Mamm. Genome 1, 78–83 (1991).
doi: 10.1007/BF02443782
Tribioli, C. et al. Methylation and sequence analysis around Eagi sites: identification of 28 new CpG islands in XQ24-XQ28. Nucleic Acids Res. 20, 727–733 (1992).
doi: 10.1093/nar/20.4.727
Duncan, C. G. et al. Dosage compensation and DNA methylation landscape of the X chromosome in mouse liver. Sci. Rep.-UK 8, 10138 (2018).
doi: 10.1038/s41598-018-28356-3
Zhu, F. et al. The interaction landscape between transcription factors and the nucleosome. Nature 562, 76–81 (2018).
doi: 10.1038/s41586-018-0549-5
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
doi: 10.1126/science.1164382
Duncan, C. G. et al. A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation. Genome Res. 22, 2339–2355 (2012).
doi: 10.1101/gr.132738.111
Wei, S. et al. Heterozygous IDH1R132H/WT created by “single base editing” inhibits human astroglial cell growth by downregulating YAP. Oncogene 37, 5160–5174 (2018).
doi: 10.1038/s41388-018-0334-9
Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).
doi: 10.1016/j.cell.2013.09.034
Jiang, P. et al. Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc. Natl Acad. Sci. USA 112, E1317–E1325 (2015).
doi: 10.1073/pnas.1500076112
Giacona, M. B. et al. Cell-free DNA in human blood plasma. Pancreas 17, 89–97 (1998).
doi: 10.1097/00006676-199807000-00012
Mouliere, F. et al. High fragmentation characterizes tumour-derived circulating DNA. PLoS ONE 6, e23418 (2011).
doi: 10.1371/journal.pone.0023418
Lapin, M. et al. Fragment size and level of cell-free DNA provide prognostic information in patients with advanced pancreatic cancer. J. Transl. Med. 16, 300 (2018).
doi: 10.1186/s12967-018-1677-2
Underhill, H. R. Leveraging the fragment length of circulating tumour dna to improve molecular profiling of solid tumour malignancies with next-generation sequencing: a pathway to advanced non-invasive diagnostics in precision oncology? Mol. Diagn. Ther. 25, 389–408 (2021).
doi: 10.1007/s40291-021-00534-6
Mouliere, F. et al. Circulating cell-free DNA from colorectal cancer patients may reveal high KRAS or BRAF mutation load. Transl. Oncol. 6, 319–IN8 (2013).
doi: 10.1593/tlo.12445
Thierry, A. R. Circulating DNA fragmentomics and cancer screening. Cell Genom. 3, 100242 (2023).
doi: 10.1016/j.xgen.2022.100242
Underhill, H. R. et al. Fragment length of circulating tumor DNA. PLoS Genet 12, e1006162 (2016).
doi: 10.1371/journal.pgen.1006162
Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002).
doi: 10.1038/nrg816
Phallen, J. et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci. Transl. Med. 9, eaan2415 (2017).
doi: 10.1126/scitranslmed.aan2415
Baylin, S. B. et al. Abnormal patterns of DNA methylation in human neoplasia: potential consequences for tumor progression. Cancer Cells Cold Spring Harb. N. Y. 1989 3, 383–390 (1991).
Gama-Sosa, M. A. et al. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 11, 6883–6894 (1983).
doi: 10.1093/nar/11.19.6883
Shen, S. Y. et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature 563, 579–583 (2018).
doi: 10.1038/s41586-018-0703-0
Li, S., Peng, Y., Landsman, D. & Panchenko, A. R. DNA methylation cues in nucleosome geometry, stability and unwrapping. Nucleic Acids Res. 50, 1864–1874 (2022).
doi: 10.1093/nar/gkac097
An, Y. et al. DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation. Nat. Commun. 14, 287 (2023).
doi: 10.1038/s41467-023-35959-6
Jensen, T. J. et al. Whole genome bisulfite sequencing of cell-free DNA and its cellular contributors uncovers placenta hypomethylated domains. Genome Biol. 16, 78 (2015).
doi: 10.1186/s13059-015-0645-x
Han, D. S. C. et al. The biology of cell-free DNA fragmentation and the roles of DNASE1, DNASE1L3, and DFFB. Am. J. Hum. Genet. 106, 202–214 (2020).
doi: 10.1016/j.ajhg.2020.01.008
Jiang, P. et al. Plasma DNA end-motif profiling as a fragmentomic marker in cancer, pregnancy, and transplantation. Cancer Discov. 10, 664–673 (2020).
doi: 10.1158/2159-8290.CD-19-0622
Annapragada, A. et al. Genome-wide repeat landscapes in cancer and cell-free DNA. Sci. Transl. Med. 16, eadj9283 (2024).
Mathios, D. et al. Detection and characterization of lung cancer using cell-free DNA fragmentomes. Nat. Commun. 12, 5060 (2021).
doi: 10.1038/s41467-021-24994-w
Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
doi: 10.1126/science.1260419
Chen, S., Zhou, Y., Chen, Y. & Gu, J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34, i884–i890 (2018).
doi: 10.1093/bioinformatics/bty560
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
doi: 10.1038/nmeth.1923
Tarasov, A., Vilella, A. J., Cuppen, E., Nijman, I. J. & Prins, P. Sambamba: fast processing of NGS alignment formats. Bioinformatics 31, 2032–2034 (2015).
doi: 10.1093/bioinformatics/btv098
Quinlan, A. R. & Hall, I. M. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).
doi: 10.1093/bioinformatics/btq033
Papp, E. et al. Integrated genomic, epigenomic, and expression analyses of ovarian cancer cell lines. Cell Rep. 25, 2617–2633 (2018).
doi: 10.1016/j.celrep.2018.10.096
Aryee, M. J. et al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30, 1363–1369 (2014).
doi: 10.1093/bioinformatics/btu049
Cavalcante, R. G. & Sartor, M. A. annotatr: genomic regions in context. Bioinformatics 33, 2381–2383 (2017).
doi: 10.1093/bioinformatics/btx183
Mathios, D. et al. Early detection of lung cancer using cfDNA fragmentation. J. Clin. Oncol. 39, 8519–8519 (2021).
doi: 10.1200/JCO.2021.39.15_suppl.8519
Peters, T. J. et al. De novo identification of differentially methylated regions in the human genome. Epigenet. Chromatin 8, 6 (2015).
doi: 10.1186/1756-8935-8-6
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
doi: 10.1093/bioinformatics/bts635
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
doi: 10.1186/s13059-014-0550-8
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
doi: 10.1073/pnas.0506580102
Liberzon, A. et al. The molecular signatures database hallmark gene set collection. Cell Syst. 1, 417–425 (2015).
doi: 10.1016/j.cels.2015.12.004
Kanehisa, M. & Goto, S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 28, 27–30 (2000).
doi: 10.1093/nar/28.1.27
Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739–1740 (2011).
doi: 10.1093/bioinformatics/btr260
Adhireksan, Z. et al. Engineering nucleosomes for generating diverse chromatin assemblies. Nucleic Acids Res. 49, gkab070 (2021).
doi: 10.1093/nar/gkab070