Extensive Chromatin Structure-Function Association Revealed by Accurate Compartmentalization Characterization

Abstract

Chromosome conformation capture-based experiments have shown that eukaryotic chromosomes are partitioned into A and B compartments conventionally identified by the first eigenvector (EV1) of dimension reduction methods. However, many genomic regions show marginal EV1 values, indicating the ambiguity of A/B compartment scheme on these regions. We develop MOSAIC (MOdularity and Singular vAlue decomposition-based Identification of Compartments), an accurate compartmental state detection scheme. MOSAIC reveals that those ambiguous regions segregate into two additional compartmental states, which typically correspond to small genomic regions flanked by large canonical A/B compartments with opposite activities. They are denoted as micro-compartments accordingly. In contrast to the canonical A/B compartments, micro-compartments cover ~30% of the genome and are highly dynamic between cell types. More importantly, distinguishing the micro-compartments underpins accurate characterization of chromatin structure-function relationship. By applying MOSAIC to GM12878 and K562 cells, we identify CD86, ILDR1 and GATA2 which show concordance between gene expression and compartmental states beyond the scheme of A/B compartments. Taken together, MOSAIC uncovers fine-scale and dynamic structures underlying canonical A/B compartments. Our results suggest dynamic chromatin compartmentalization is underlying transcriptional regulation and disease.