Systematic Evaluation of the Heterogeneity of Topologically Associating Domain Boundaries in a Large Genomic Context in Humans

Topologically associating domains (TADs) are generally considered as a homogeneous basic units of genome folding, which is critical for transcriptional regulation. However, recent studies indicate that both the TAD domain structures and the boundaries between them are not as homogeneous as originally recognized. Here, we address the heterogeneity of the TAD boundaries in the human genome at a large scale, which varies between active and inactive chromatin and across cell lines and tissues. To address this, based on the well-annotated TAD boundaries extracted from multiple cell lines and tissues, we examine their nucleotide content, resulting in two main clusters, one GC-rich and one AT-rich, which are mainly distributed in active and inactive chromatin, respectively. Also, they contain different types of repetitive sequences and have different epigenetic patterns, with more CTCF binding motifs in the GC-rich cluster. Hence, our observations of the TAD boundary content provide novel insights into TAD genomic architecture. In addition, we find that cell- or tissue-specific boundaries are less evolutionarily conserved than other boundaries. We highlight the importance of TAD boundary diversity in different functional contexts and discuss the importance of the different types of repetitive sequences and epigenetic patterns in the two main types of boundaries.