Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection

Ulz, Peter; Perakis, Samantha; Zhou, Qing; Moser, Tina; Belic, Jelena; Lazzeri, Isaac; Wölfler, Albert; Zebisch, Armin; Gerger, Armin; Pristauz, Gunda; Petru, Edgar; White, Brandon; Roberts, Charles E. S.; John, John St.; Schimek, Michael G.; Geigl, Jochen B.; Bauernhofer, Thomas; Sill, Heinz; Bock, Christoph; Heitzer, Ellen; Speicher, Michael R.

doi:10.1038/s41467-019-12714-4

Cited by 178 publications

(187 citation statements)

References 46 publications

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“…Using the cfNOMe approach, nucleosome occupancy studies are turned from an expensive add-on test into an inexpensive in silico analysis step, bringing them closer to a broader clinical application. Consequently, one major takeaway of this study is whenever cfDNA methylome data is being generated in this way, investigators should also take the opportunity to look at its fragmentation patterns for additional insight, e.g., as was recently demonstrated by Ulz and colleagues in a cancer context [15].…”

Section: Discussionmentioning

confidence: 99%

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cfNOMe — A single assay for comprehensive epigenetic analyses of cell-free DNA

et al. 2020

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Cell-free DNA (cfDNA) analysis has become essential in cancer diagnostics and prenatal testing. We present cfNOMe, a two-in-one method of measuring cfDNA cytosine methylation and nucleosome occupancy in a single assay using non-disruptive enzymatic cytosine conversion and a custom bioinformatic pipeline. We show that enzymatic cytosine conversion better preserves cfDNA fragmentation information than does bisulfite conversion. Whereas previously separate experiments were required to study either epigenetic marking, cfNOMe delivers reliable results for both, enabling more comprehensive and inexpensive epigenetic cfDNA profiling. cfNOMe has the potential to advance biomarker discovery and diagnostic usage in diseases with systemic perturbations of cfDNA composition.

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Section: Discussionmentioning

confidence: 99%

“…Such measurements of NO have been successfully used to infer the gene expression [14] and regulation [3] landscapes of the cfDNA's tissue-of-origin. Most recently, a similar approach was reported to identify cell lineage-specific transcription factor binding for the prediction of tumor subtypes in prostate cancer [15].…”

Section: Introductionmentioning

confidence: 99%

cfNOMe — A single assay for comprehensive epigenetic analyses of cell-free DNA

et al. 2020

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“…More recent approaches leverage epigenetic information in cell free DNA. Extremely deep sequencing of total cfDNA to identify nucleosomes and transcription factors positions 19,75 and occupancy 18 Specifically, the levels of H3K4me3 correlate with gene expression ( Figures 2C and 4A), which allow us to infer transcriptional activity in cells of origin. Therefore, assaying chromatin marks in cf-nucleosomes provides rich and complex information beyond current methodologies.…”

Section: Discussionmentioning

confidence: 99%

ChIP-seq of plasma cell-free nucleosomes identifies cell-of-origin gene expression programs

Sadeh¹,

Sharkia²,

Fialkoff³

et al. 2019

Preprint

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Blood cell-free DNA (cfDNA) is derived from fragmented chromatin in dying cells. As such, it remains associated with histones that may retain the covalent modifications present in the cell of origin. Until now this rich epigenetic information carried by cell-free nucleosomes has not been explored at the genome level. Here, we perform ChIP-seq of cell free nucleosomes (cfChIP-seq) directly from human blood plasma to sequence DNA fragments from nucleosomes carrying specific chromatin marks. We assay a cohort of healthy subjects and patients and use cfChIP-seq to generate rich sequencing libraries from low volumes of blood. We find that cfChIP-seq of chromatin marks associated with active transcription recapitulates ChIP-seq profiles of the same marks in the tissue of origin, and reflects gene activity in these cells of origin. We demonstrate that cfChIP-seq detects changes in expression programs in patients with 1 heart and liver injury or cancer. cfChIP-seq opens a new window into normal and pathologic tissue dynamics with far-reaching implications for biology and medicine. One Sentence Summary:Chromatin immunoprecipitation and sequencing of histone modifications on blood-circulating nucleosomes (cfChIP-seq) provides detailed information about gene expression programs in different human organs.

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“…The size of cfDNA fragments differs according to their tissues-of-origin, including differences between fetal and maternal DNA, and between tumor and non-tumor derived DNA (Snyder et al, 2016). The cfDNA fragmentation patterns and their derived patterns from whole-genome sequencing (WGS), such as nucleosome positions, patterns near transcription start sites or transcription factor binding sites, ended position of cfDNA, fragmentation hotspots, co-fragmentation patterns, and large-scale fragmentation changes at mega-base level, offer extensive signals from the diseased tissues, as well as possible alterations from peripheral immune cell deaths, which can significantly increase the sensitivity for disease diagnosis (Snyder et al, 2016;Ulz et al, 2016;Jiang et al, 2018;Cristiano et al, 2019;Ulz et al, 2019;Sun et al, 2019;Liu et al, 2019;Zhou and Liu, 2020).…”

Section: Introductionmentioning

confidence: 99%

FinaleDB: a browser and database of cell-free DNA fragmentation patterns

Zheng

Zhu

Liu

2020

Preprint

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SummaryCirculating cell-free DNA (cfDNA) is a promising biomarker for the diagnosis and prognosis of many diseases, including cancer. The genome-wide non-random fragmentation patterns of cfDNA are associated with the nucleosomal protection, epigenetic environment, and gene expression in the cell types that contributed to cfDNA. However, current progress on the development of computational methods and understanding of molecular mechanisms behind cfDNA fragmentation patterns is significantly limited by the controlled-access of cfDNA whole-genome sequencing (WGS) dataset. Here, we present FinaleDB (FragmentatIoN AnaLysis of cEll-free DNA DataBase), a comprehensive database to host thousands of uniformly processed and curated de-identified cfDNA WGS datasets across different pathological conditions. Furthermore, FinaleDB comes with a fragmentation genome browser, from which users can seamlessly integrate thousands of other omics data in different cell types to experience a comprehensive view of both gene-regulatory landscape and cfDNA fragmentation patterns.Availability and implementationFinaleDB service: http://finaledb.research.cchmc.org/ FinaleDB source code: https://github.com/epifluidlab/finaledb_portal and https://github.com/epifluidlab/finaledb_workflow.Contactlyping1986@gmail.com

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Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection

Cited by 178 publications

References 46 publications

cfNOMe — A single assay for comprehensive epigenetic analyses of cell-free DNA

cfNOMe — A single assay for comprehensive epigenetic analyses of cell-free DNA

ChIP-seq of plasma cell-free nucleosomes identifies cell-of-origin gene expression programs

FinaleDB: a browser and database of cell-free DNA fragmentation patterns

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