Abstract
A myriad of diseases is caused or characterized by alteration of epigenetic patterns, including changes in DNA methylation, post-translational histone modifications, or chromatin structure. These changes of the epigenome represent a highly interesting layer of information for disease stratification and for personalized medicine. Traditionally, epigenomic profiling required large amounts of cells, which are rarely available with clinical samples. Also, the cellular heterogeneity complicates analysis when profiling clinical samples for unbiased genome-wide biomarker discovery. Recent years saw great progress in miniaturization of genome-wide epigenomic profiling, enabling large-scale epigenetic biomarker screens for disease diagnosis, prognosis, and stratification on patient-derived samples. All main genome-wide profiling technologies have now been scaled down and/or are compatible with single-cell readout, including: (i) Bisulfite sequencing to determine DNA methylation at base-pair resolution, (ii) ChIP-Seq to identify protein binding sites on the genome, (iii) DNaseI-Seq/ATAC-Seq to profile open chromatin, and (iv) 4C-Seq and HiC-Seq to determine the spatial organization of chromosomes. In this review we provide an overview of current genome-wide epigenomic profiling technologies and main technological advances that allowed miniaturization of these assays down to single-cell level. For each of these technologies we evaluate their application for future biomarker discovery. We will focus on (i) compatibility of these technologies with methods used for clinical sample preservation, including methods used by biobanks that store large numbers of patient samples, and (ii) automation of these technologies for robust sample preparation and increased throughput.
Highlights
The epigenome Within a eukaryotic cell, the Deoxyribonucleic acid (DNA) is packaged to fit into the small volume of the nucleus in a highly organized fashion
Molecular biomarkers possess a critical advantage over more traditional biomarkers during the exploratory phase of biomarker discovery, as many candidate molecular biomarkers can be assayed in parallel
Subsequent compaction leads to higher order structures including the formation of very dense arrays of nucleosomes observed in heterochromatin [12, 13]
Summary
Within fundamental and clinical research and in clinical practice, biomarkers play an important role to facilitate disease diagnosis, prognosis, and selection of targeted therapies in patients. Molecular biomarkers possess a critical advantage over more traditional biomarkers during the exploratory phase of biomarker discovery, as many candidate molecular biomarkers can be assayed in parallel This involves screening of (epi)genomic features at a genome-wide scale, often making use of powerful next-generation sequencing (NGS)-based technologies. In the second part of this review, we will focus on current genome-wide epigenomic profiling technologies, and whether these are already or will likely become compatible with biomarker discovery in the near future We will evaluate these approaches with three criteria in mind: (i) the possibility to use frozen or chemically fixed material in these assays, (ii) compatibility with miniaturization and single-cell profiling, and (iii) the current level of automation
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