Long range epigenetic silencing is a trans‐species mechanism that results in cancer specific deregulation by overriding the chromatin domains of normal cells

Abstract

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.

Overlapping DNA Methylation Dynamics in Mouse Intestinal Cell Differentiation and Early Stages of Malignant Progression

“…The nature and functional implications of DMDs are unknown. Nevertheless, it is tempting to compare hypermethylated DMDs with the well characterized Long Range Epigenetic Silencing (LRES) phenomenon initially described in human colorectal cancer [ 48 ] and also found in murine tumors [ 72 ]. LRES appears as the concurrent hypermethylation of multiple CpG islands and downregulation of most of the genes in a genomic region ranging from hundreds of kilobases to a few megabases [ 73 ].…”

“…It should be noted that AIMS-Seq is not the most appropriate method to detect epigenetic changes affecting large chromosomal regions due to the interspersed nature of its genomic coverage. Specific regional analyses are required to clarify the nature of DMDs as it was done for LRES in different settings [ 48 , 71 , 72 , 74 , 75 , 76 ]. On the other hand, genome-wide approaches have identified large chromosomal domains undergoing extensive DNA hypomethylation in human colorectal cancer [ 64 , 65 ].…”

Integrated analyses of DNA methylation and hydroxymethylation reveal tumor suppressive roles of ECM1, ATF5, and EOMESin human hepatocellular carcinoma

“…Although we currently have no direct evidence that the methylation and hydroxymethylation changes in DMR and DhMR genes may directly contribute to the activation of these pathways, these two types of DNA modifications represent essential participants in heptocarcinogenesis. In addition to gene transcription repression, DNA modifications may also be important for alternative splicing [ 34 ], gene mutation [ 35 ], and chromatin remodeling [ 36 ] in tumorigenesis. Further studies are needed to examine these genes.…”

The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

“…Besides the large blocks of DNA hypomethylation (Hansen et al 2011;Berman et al 2012;Hon et al 2012;Timp et al 2014) and hypermethylation Coolen et al 2010;Forn et al 2013), other alterations as the activation of gene clusters (Bert et al 2013) and the increased somatic mutation rates observed in heterochromatic and late replicating regions (Schuster-Böckler and Lehner 2012;Polak et al 2015) point out that factors regulating high-order chromatin architecture (Dekker et al 2013;Gómez-Díaz and Corces 2014;Feinberg et al 2016) might play a principal role in the remodeling of the cancer genome (Rodriguez et al 2008a;Lizardi et al 2011;Kemp et al 2014;Lay et al 2015;Taberlay et al 2016). The contribution of Alu repeats to the setting and maintenance of chromatin domains and their regulation in normal and cancer cells is still unknown.…”

“…The reprogramming of regulatory circuits arises as a direct consequence of genetic and epigenetic changes. Similarly to genetic aberrations, that may affect a single gene (e.g., a point mutation) or large chromosomal regions (e.g., losses of heterozygosity), cancer cells show epigenetic alterations involving the misregulation of a single gene (e.g., expression silencing by hypermethylation of the promoter CpG island) (Esteller 2007;Jones 2012) or large chromosomal regions (i.e., long-range epigenetic silencing) Coolen et al 2010;Forn et al 2013). Although local alterations are excellent pointers for the identification of candidate cancer genes, alterations affecting large chromosomal regions offer limited clues about both the mechanisms underlying the alteration and also the functional impact of the alteration on the disease.…”