Table 2.

Computational tools for the assessment of chromatin hierarchy.

Tools		Function	References
Common to both higher- and primary-order assessment
Aligners Bowtie2 BWA SOAP RMAP Cloudburst SHRiMP		-Ultrafast, sensitive, accurate and memory-efficient gapped read aligner. -Maps low-divergent sequences against a large reference genome. -Efficient gapped and ungapped alignment of short oligonucleotides to reference. -Maps reads from short-read sequencing technology. -Parallel read-mapping algorithm optimized for mapping NGS data. -Fully gapped local alignment of short reads to targets.	[114] [58] [59] [91] [80] [77]
Higher-order
4C FourCSeq		-Uses R to detect specific interactions between DNA elements and identify differential interactions between conditions.	[115]
5C HiFive		-A Python package for normalization and analysis of chromatin structural data produced using either the 5C of HiC assay.	[79]
Hi-C Fit-Hi-C GOTHiC HOMER HIPPIE HiCCUPS HiCPipe Juicer		-Assigns statistical confidence to mid-range cis-chromosomal contacts. -Models contact-frequency uncertainty as binomial distribution. -Designed for high-resolution Hi-C data. -Identifies chromatin interactions in a genome. -Detect sub-TAD chromatin interactions (cis). -Provides scripts and programs that correct Hi-C contact maps. -Aligns, filters and normalizes, identifies and compares TADs, loops and compartments and display using Juicebox.	[7] [116] [41,42] [46] [71] [104] [29,30]
HiGlass		-Enables multiscale navigation of TAD interactions along with 1D genomic tracks	[52]
TAD calling TADbit TADtree Armatus		-TADbit includes quality control module, and aligns reads to the reference. -Identifies hierarchical topological domains. -Uses dynamic programming to call TADs in different resolutions.	[84] [102] [33]
Primary-order
Primary assessment ArchTEX DANPOS-profile CEAS Artemis EagleView Integrative Genomics Viewer		-Java-based tool for identification of optimal extension of sequence tags. -Dynamic nucleosome analysis at single-nucleotide resolution. -Provides statistics on fragment enrichment in important genomic regions. -Java-based free genome browser, annotation and visualization tool. -Viewer for next-generation genome assembles with data integration capability. -Lightweight visualization tool for intuitive real-time exploration of diverse data.	[56] [19] [87] [78] [117] [118]
Peak-calling MNase-seq	GeneTrack iNPS DANPOS	-Employs Gaussian smoothing for nucleosome calling. -Detects nucleosomes from the first derivative of the Gaussian smoothed profile. -Allows comparison of datasets and identification of dynamic nucleosomes.	[4] [20] [19]
DNase-seq	MACS2 Hotspot F-seq ZINBA	-Models length of DNA fragments for spatial resolution of predicted binding sites. -Identifies regions of local enrichment of short-read sequence tags. -Identifies chromatin accessible regions and tentative TF footprints. -Generates peak calls that are consistent with known biological patterns.	[106] [49] [14,15] [72]
FAIRE-seq	MACS2 ZINBA	-Models length of DNA fragments for spatial resolution of predicted binding site. -Generates peak calls that are consistent with known biological patterns.	[106] [72]
ATAC-seq	MACS2 Hotspot HOMER F-seq ZINBA	-Models length of DNA fragments for spatial resolution of predicted binding site. -Identifies regions of local enrichment of short-read sequence tags. -Motif discovery and transcript identification analysis. -Identifies chromatin accessible regions and tentative TF footprints. -Generates peak calls that are consistent with known biological patterns.	[14,15] [106] [49] [41,42] [72]
Accessibility analysis CENTIPEDE V-Plots DNase2TF		-Infers regions of the genome bound by transcription factors. -Plots to reveal chromatin features of transcription factor binding sites. -Footprinting algorithm with accurate detection and less computing time.	[67,68] [43] [94]