Computational characterization of chromatin domain boundary-associated genomic elements

Abstract

Topologically associated domains (TADs) are 3D genomic structures with high internal interactions that play important roles in genome compaction and gene regulation. Their genomic locations and their association with CCCTC-binding factor (CTCF)-binding sites and transcription start sites (TSSs) were recently reported. However, the relationship between TADs and other genomic elements has not been systematically evaluated. This was addressed in the present study, with a focus on the enrichment of these genomic elements and their ability to predict the TAD boundary region. We found that consensus CTCF-binding sites were strongly associated with TAD boundaries as well as with the transcription factors (TFs) Zinc finger protein (ZNF)143 and Yin Yang (YY)1. TAD boundary-associated genomic elements include DNase I-hypersensitive sites, H3K36 trimethylation, TSSs, RNA polymerase II, and TFs such as Specificity protein 1, ZNF274 and SIX homeobox 5. Computational modeling with these genomic elements suggests that they have distinct roles in TAD boundary formation. We propose a structural model of TAD boundaries based on these findings that provides a basis for studying the mechanism of chromatin structure formation and gene regulation.

Identifying regulatory and spatial genomic architectural elements using cell type independent machine and deep learning models

“…Many models and computational approaches have been developed to predict chromatin interactions and topological domain boundaries. These include an eclectic collection of computational methods including TADLactua [88], PCGS [89], nTDP [90] and BART [80]. TADLacuta utilised random forest and deep learning methods and integrated histone modifications, CTCF binding and transcription factor motifs predict TAD boundaries with an AUC ROC accuracy 0.867 [88].…”

“…This may explain why in our analysis HICRs contain elements with both active and inactive modifications indicating that these potential EPI regions may contain a mixture of active, inactive, poised and primed enhancer and promoter elements. Hong et al, [89] developed population greedy search algorithm (PGSA) to identify boundary enriched motifs and concluded that in addition to CTCF other TF such as ZNF143, ZNF274, YY1, SP1, ZNf274 and chromatin accessibility (DHS) as well as epigenetic modifications H3K36me3, gene associated features and protein complexes such as RNA PolII, TSSs were all enriched at TAD boundaries. Similarly Sefer and Kingsford developed a convex semi-nonparametric approach called nTDP based on Bernstein polynomials to explore the joint effects of histone markers on TAD formation [90].…”

TopicNet: a framework for measuring transcriptional regulatory network change

“…On the contrary, TFs with more constant roles such as NR2C2 (O'Geen et al, 2010) show very little difference between cell types. Interestingly, ZNF274 and SIX5, which were shown to relate to CTCF binding sites (Hong and Kim, 2017), also have low specificity similar to CTCF. Fig s5 lists the individual rewiring events with top values.…”

Lessons from the analysis of TAD boundary deletions in normal population

“…preventing chromatin inter-domain interactions. They show not only enrichment in binding sites for DNA-binding proteins, such as CTCF, ZNF143, SMC, and YY1 but also specific histone epigenetic modifications, such as H3K36 trimethylation (H3K36me3), and Transcription Starting Sites (TSS) of housekeeping genes (Hong and Kim 2017).…”