Epigenetic Conservation Infers That Colorectal Cancer Progenitors Retain The Phenotypic Plasticity Of Normal Colon

Abstract

Abstract Plasticity, or the ability to rapidly and reversibly change phenotypes, may help explain how a single progenitor cell eventually generates a tumor with many different cell phenotypes. We developed a quantitative signal of plasticity that correlates epigenetic gene conservation with single cell expression variability to see if normal colon crypt plasticity is retained during tumorigenesis. The question is whether more variably expressed genes have more, or less epigenetic variation. In normal colon crypts, greater epigenetic conservation was present in more variably expressed genes, consistent with plasticity where the epigenome is conserved and broadly permissive, and expression is determined by the microenvironment and not by epigenetic remodeling. Consistent with retention of this plasticity, more variably expressed genes were even more conserved in 4 adenomas and 17 cancers. Epigenetic configurations permissive for variable gene expression are present at the start of growth. A progenitor that starts with plasticity can readily generate, as needed, progeny with many phenotypes and is poised for rapid growth.