Retrieving the topology of chromatin domains from deep sequencing data with correlation functions

Abstract

Epigenetic modifications and other chromatin features partition the genome on multiple length scales. They define chromatin domains with distinct biological functions that come in sizes ranging from single modified DNA bases to several megabases in case of heterochromatic histone modifications. Due to chromatin folding, domains that are well separated along the linear nucleosome chain can form long-range interactions in three-dimensional space. It has now become a routine task to map epigenetic marks and chromatin structure by deep sequencing methods. However, assessing and comparing the properties of chromatin domains and their positional relationships across data sets without a priori assumptions remains challenging. Here, we introduce multi-scale correlation evaluation (MCORE), which uses the fluctuation spectrum of mapped sequencing reads to quantify and compare chromatin patterns over a broad range of length scales in a model-independent manner. We applied MCORE to map the chromatin landscape in mouse embryonic stem cells and differentiated neural cells. We integrated sequencing data from chromatin immunoprecipitation, RNA expression, DNA methylation and chromosome conformation capture experiments into network models that reflect the positional relationships among these features on different genomic scales. Furthermore, we used MCORE to compare our experimental data to models for heterochromatin reorganization during differentiation. The application of correlation functions to deep sequencing data complements current evaluation schemes and will support the development of quantitative descriptions of chromatin networks.