Mar 28, 2020

Loss of APC Rapidly Impairs DNA Methylation Programs and Cell Fate Decisions in LGR5+ Intestinal Stem Cells

Cancer Research
Marco BruschiPhilippe Jay

Abstract

Colorectal cancer (CRC) initiation and progression result from the accumulation of genetic and epigenetic alterations. Although aberrant gene expression and DNA methylation profiles are considered hallmarks of CRC development, the precise timing at which these are produced during tumor establishment remains elusive. Here we investigated the early transcriptional and epigenetic changes induced by Apc inactivation in intestinal crypts. Hyper-activation of the Wnt pathway via Apc inactivation in crypt base columnar (CBC) intestinal stem cells (ISC) led to their rapid accumulation driven by an impaired molecular commitment to differentiation, which was associated with discrete alterations in DNA methylation. Importantly, inhibiting the enzymes responsible for de novo DNA methylation restored the responsiveness of Apc-deficient intestinal organoids to stimuli regulating the proliferation-to-differentiation transition in ISC. This work reveals that early DNA methylation changes play critical roles in the establishment of the impaired fate decision program consecutive to Apc loss-of-function.

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Mentioned in this Paper

APC gene
DNA
Wnt Signaling Pathway
WNT1
Hyperactive Behavior
APC
Neoplasms
DNA Methylation
Gene Expression
Colorectal Cancer

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