Proximity ligation based techniques, like HiC, involve restriction digestion followed by ligation of formaldehyde cross-linked chromatin. Through analysis of lamina-associated domains (LADs), inactive X-chromosome in mammals and polytene bands in fly, we first established that the DNA in condensed chromatin had lesser accessibility to restriction endonucleases used in HiC as compared to that in decondensed chromatin. The observed bias was independent of known systematic biases, was not appropriately corrected by existing computational methods, and needed an additional optimization step. We then repurposed this bias to identify novel condensed domains outside LADs, which were bordered by insulators and were dynamically associated with the developmentally regulated epigenetic and transcriptional states. Our observations suggested that the corrected one-dimensional read counts of existing HiC datasets can be reliably repurposed to study the gene-regulatory dynamics associated with chromatin condensation and decondensation.

Repurposing the biased visibility in HiC datasets to mark dynamically regulated condensed and decondensed chromatin states genome-wide