NucPosDB: a database of nucleosome positioning in vivo and nucleosomics of cell-free DNA

Mariya Shtumpf,Kristan V Piroeva,Shivam P Agrawal,Vladimir B Teif,Divya R Jacob

doi:10.1007/s00412-021-00766-9

Abstract

Nucleosome positioning is involved in many gene regulatory processes happening in the cell, and it may change as cells differentiate or respond to the changing microenvironment in a healthy or diseased organism. One important implication of nucleosome positioning in clinical epigenetics is its use in the “nucleosomics” analysis of cell-free DNA (cfDNA) for the purpose of patient diagnostics in liquid biopsies. The rationale for this is that the apoptotic nucleases that digest chromatin of the dying cells mostly cut DNA between nucleosomes. Thus, the short pieces of DNA in body fluids reflect the positions of nucleosomes in the cells of origin. Here, we report a systematic nucleosomics database — NucPosDB — curating published nucleosome positioning datasets in vivo as well as datasets of sequenced cell-free DNA (cfDNA) that reflect nucleosome positioning in situ in the cells of origin. Users can select subsets of the database by a number of criteria and then obtain raw or processed data. NucPosDB also reports the originally determined regions with stable nucleosome occupancy across several individuals with a given condition. An additional section provides a catalogue of computational tools for the analysis of nucleosome positioning or cfDNA experiments and theoretical algorithms for the prediction of nucleosome positioning preferences from DNA sequence. We provide an overview of the field, describe the structure of the database in this context, and demonstrate data variability using examples of different medical conditions. NucPosDB is useful both for the analysis of fundamental gene regulation processes and the training of computational models for patient diagnostics based on cfDNA. The database currently curates ~ 400 publications on nucleosome positioning in cell lines and in situ as well as cfDNA from > 10,000 patients and healthy volunteers. For open-access cfDNA datasets as well as key MNase-seq datasets in human cells, NucPosDB allows downloading processed mapped data in addition to the regions with stable nucleosome occupancy. NucPosDB is available at https://generegulation.org/nucposdb/.

Highlights

Genomic nucleosome positions are non-random and unique for each cell, reflecting many biological processes that require the access of regulatory molecules to the DNA)
Different biological processes such as NETosis may employ a different combination of enzymes; it may be possible to distinguish medical conditions that are characterised by inflammation
NucPosDB offers a user-friendly interface and curates published in vivo nucleosome positioning datasets including > 18 types of experimental techniques in > 16 different species and distinct cell types, supplemented with the repository curating cell-free DNA (cfDNA) datasets for more than 10,000 patients as well as the software packages for “nucleosomics” analysis

Summary

Background

Genomic nucleosome positions are non-random and unique for each cell, reflecting many biological processes that require the access of regulatory molecules to the DNA (e.g. reviewed in Clarkson et al 2019; Baldi et al 2020; Parmar and Padinhateeri 2020)). We will show below that even within a narrow group of medical conditions, the distribution of cfDNA sizes is quite heterogeneous Another type of fragmentomics analysis is based on the fact that DNA nucleases have different sequence preferences (Serpas et al 2019; Han et al 2020) and the distribution of nucleotide patterns at the ends of the cfDNA fragments may provide valuable diagnostic information (van der Pol and Mouliere 2019). It contains the following sections: (1) nucleosome positioning in vivo, (2) sequenced cfDNA, (3) database of regions in the human genome with stable nucleosome occupancy for a given condition, and the repository of software for nucleosomics, further separated into three subsections devoted to (4) analysis of nucleosome maps in vivo, (5) prediction of nucleosome formation preferences based on DNA sequence and (6) cfDNA-specific analysis. The relative deviation was defined as the ratio of the standard deviation to the normalised nucleosome occupancy in a given window

Findings

Utility and discussion

Conclusions