Nucleosome dynamics in human colorectal cancer specimens reveal activation of a CNOT3-regulated pathway of embryonic stem cell self-renewal

Temporal chromatin dynamics can reveal transcriptional determinants of cell differentiation, and we reasoned that dynamic changes in nucleosome configuration might similarly disclose transcriptional regulators in cancer. To this end, we identified thousands of cis-regulatory sites where chromatin marks and configuration in human CRCs differed from those in their respective precursor adenomas. (based on H3K4me2 mark).At such sites in selected cases, we observed an abundance of sequence motifs and binding of CNOT3, which is overexpressed in scattered tumor cells in cases associated with unfavorable prognosis. In primary CRCs and cell lines, CNOT3 binding is highly enriched at genes that correspond to both the active and silenced limbs of the ESC gene signature expressed in aggressive carcinomas and these arms respond in coordinated, opposite fashion to CNOT3 loss.