Albert Einstein Cancer Center

Altered Dynamics of Intestinal Cell Maturation in Apc1638N/+ Mice

Studies by AECC members Augenlicht, Singer and colleagues using novel imaging of active transcription sites in interphase nuclei of intestinal epithelial cells in situ, showed that key genes associated with Wnt and Notch signaling were dynamically regulated as the cells underwent normal maturation during their migration along the mouse crypt-villus axis. However, oscillating patterns of activation of these genes were displaced along this axis in the histologically normal intestinal mucosa of Apc(1638N/+) mice before tumor development. Gene expression profiling then showed that the normal reprogramming of cells along the crypt-villus axis was dampened in the Apc(1638N/+) mice, with an overrepresentation of c-myc target genes among those loci affected in the mutant mice. Moreover, in the Apc(1638N/+) mice, there was a perturbed pattern of expression of lineage-specific markers along the crypt-villus axis consistent with transcription site repression of the Math1 gene, and genes encoding enzymes of every step of the tricarboxylic acid cycle were downregulated in the crypt of Apc(1638N/+) mice compared with wild-type, but not in the villus. The authors suggested that these changes may alter energy metabolism and generate a pseudohypoxic state, consistent with elevated expression of Hif1alpha and its target genes. Thus, although intestinal tumors develop in Apc(1638N/+) mice on focal loss or inactivation of the WT allele, these results show that in the Apc(1638N/+) mouse, inheritance of only a single WT Apc allele perturbs the dynamic and complex reprogramming underlying normal cell maturation, which links epithelial function and homeostasis with architectural organization of the intestine. 

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