DNA methylation and chromatin remodeling are frequently implicated in the 
silencing of genes involved in carcinogenesis. Long Range Epigenetic Silencing 
(LRES) is a mechanism of gene inactivation that affects multiple contiguous CpG 
islands and has been described in different human cancer types. However, it is 
unknown whether there is a coordinated regulation of the genes embedded in these 
regions in normal cells and in early stages of tumor progression. To better 
characterize the molecular events associated with the regulation and remodeling 
of these regions we analyzed two regions undergoing LRES in human colon cancer 
in the mouse model. We demonstrate that LRES also occurs in murine cancer in 
vivo and mimics the molecular features of the human phenomenon, namely, 
downregulation of gene expression, acquisition of inactive histone marks, and 
DNA hypermethylation of specific CpG islands. The genes embedded in these 
regions showed a dynamic and autonomous regulation during mouse intestinal cell 
differentiation, indicating that, in the framework considered here, the 
coordinated regulation in LRES is restricted to cancer. Unexpectedly, benign 
adenomas in Apc(Min/+) mice showed overexpression of most of the genes affected 
by LRES in cancer, which suggests that the repressive remodeling of the region 
is a late event. Chromatin immunoprecipitation analysis of the transcriptional 
insulator CTCF in mouse colon cancer cells revealed disrupted chromatin domain 
boundaries as compared with normal cells. Malignant regression of cancer cells 
by in vitro differentiation resulted in partial reversion of LRES and gain of 
CTCF binding. We conclude that genes in LRES regions are plastically regulated 
in cell differentiation and hyperproliferation, but are constrained to a 
coordinated repression by abolishing boundaries and the autonomous regulation of 
chromatin domains in cancer cells.