Global decay of regulatory chromatin architecture promotes rebalancing of gene expression during colorectal cancer development [RNA-seq II]

Although the 3D genome architecture is essential for long-range gene regulation, the significance of physical chromatin interactions is challenged by recent findings of mutual insensitiveness between contact propensity and gene expression. Here we report hundred basepair-resolution profiling of chromatin conformation in 33 colon tissues tracing the formation and malignant transformation of colorectal polyps. We identified progressive genome-wide decays of chromatin structures such as interaction stripes and loops on all types of cis-regulatory elements, particularly promoters, independent to the alterations of DNA methylation and chromatin accessibility. Instead of linearly correlated with degree of structural decays, transcription levels shifted toward correction of their quantitative mismatching with corresponding promoter contact propensity. These observations suggest increasing sensitivity of transcription to regulatory architecture integrity along with its loss during early cancer development, a mechanism which may provide novel insights to the misregulations of cancer driving genes. Overall design: mRNA-seq was performed on three colon organoids (1 unaffected mucosa, 2 adenomatous polyps), HT29, HCT116, and primary human colon epithelial cell lines. Differential gene expression analyses were performed for each sample with our without 24 hours of 500 JQ1 treatment. Each sample and condition includes two biological replicates.