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Because the traditional Hi-C technique uses a 6-bp restriction enzyme to cut chromatin, which usually finds one cleavage site every 5000bp in the genome, it does not have sufficient resolution for identification of enhancer-promoter interactions. Significant improvement has been achieved by the in situ Hi-C protocol, which uses a 4-bp cutter enzyme and reaches a resolution of about 1kb, thus enabling identification of specific enhancer-promoter interactions at high-resolution. However, this method requires a costly sequencing depth of 5 to 10 billions of paired-end tags (PETs) per library, which prohibits its application to a large number of samples. Other 3C-based techniques have been developed to focus on interactions at selected regions by capture Hi-C or tethered through specific proteins by ChIA-PET have helped to increase resolution by focusing on potential regulatory regions of the genome. 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