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Title: Repetitive elements and enforced transcriptional repression co-operate to enhance DNA methylation spreading into a promoter CpG-island

Author
item ZHANG, YAN - Md Anderson Cancer Center
item SHU, JINGMIN - Md Anderson Cancer Center
item SI, JIALI - Md Anderson Cancer Center
item SHEN, LANLAN - Children'S Nutrition Research Center (CNRC)
item ESTECIO, MARCOS - Md Anderson Cancer Center
item ISSA, JEAN-PIERRE - Md Anderson Cancer Center

Submitted to: Nucleic Acids Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/24/2012
Publication Date: 8/1/2012
Citation: Zhang, Y., Shu, J., Si, J., Shen, L., Estecio, M.R., Issa, J.J. 2012. Repetitive elements and enforced transcriptional repression co-operate to enhance DNA methylation spreading into a promoter CpG-island. Nucleic Acids Research. 40(15):7257-7268.

Interpretive Summary: Mammalian development requires the establishment of hundreds of different cell types, each with specific gene-expression patterns. DNA methylation (a type of chemical modification of DNA) provides an epigenetic mechanism that the cell uses to control gene expression. A long-standing mystery however is how the methylated DNAs across the genome are targeted. This research seeks to understand fundamental mechanisms regulating the establishment of DNA methylation patterns. We discovered specific DNA sequence services as a "signal" for the generation of DNA methylation pattern. Our research provides novel insights into the mechanism of epigenetic gene regulation and the design of epigenetic reprogramming.

Technical Abstract: Repression of many tumor suppressor genes in cancer is concurrent with aberrantly increased DNA methylation levels at promoter CpG islands (CGIs). About one-fourth of empirically defined human promoters are surrounded by or contain clustered repetitive elements. It was previously observed that a sharp transition of methylation exists between highly methylated repetitive elements and unmethylated promoter-CGIs in normal tissues. The factors that lead to aberrant CGI hypermethylation in cancer remain poorly understood. Here, we established a site-specific integration system with enforced local transcriptional repression in colorectal cancer cells and monitored the occurrence of initial de novo methylation at specific CG sites adjacent to the CGI of the INSL6 promoter, which could be accelerated by binding a KRAB-containing transcriptional factor. Additional repetitive elements from P16 and RIL (PDLIM4), if situated adjacent to the promoter of INSL6, could confer DNA methylation spreading into the CGI particularly in the setting of KRAB-factor binding. However, a repressive chromatin alone was not sufficient to initiate DNA methylation, which required specific DNA sequences and was integration-site (and/or cell-line) specific. Overall, these results demonstrate a requirement for specific DNA sequences to trigger de novo DNA methylation, and repetitive elements as cis-regulatory factors to cooperate with advanced transcriptional repression in promoting methylation spreading.