Chromatin Inactivation Precedes De Novo DNA Methylation during the Progressive Epigenetic Silencing of the RASSF1A Promoter Export

@article{citeulike:6056390, abstract = {Epigenetic inactivation of the RASSF1A tumor suppressor by CpG island methylation was frequently detected in cancer. However, the mechanisms of this aberrant DNA methylation are unknown. In the RASSF1A promoter, we characterized four Sp1 sites, which are frequently methylated in cancer. We examined the functional relationship between DNA methylation, histone modification, Sp1 binding, and RASSF1A expression in proliferating human mammary epithelial cells. With increasing passages, the transcription of RASSF1A was dramatically silenced. This inactivation was associated with deacetylation and lysine 9 trimethylation of histone H3 and an impaired binding of Sp1 at the RASSF1A promoter. In mammary epithelial cells that had overcome a stress-associated senescence barrier, a spreading of DNA methylation in the CpG island promoter was observed. When the RASSF1A-silenced cells were treated with inhibitors of DNA methyltransferase and histone deacetylase, binding of Sp1 and expression of RASSF1A reoccurred. In summary, we observed that histone H3 deacetylation and H3 lysine 9 trimethylation occur in the same time window as gene inactivation and precede DNA methylation. Our data suggest that in epithelial cells, histone inactivation may trigger de novo DNA methylation of the RASSF1A promoter and this system may serve as a model for CpG island inactivation of tumor suppressor genes. 10.1128/MCB.25.10.3923-3933.2005}, author = {Strunnikova, Maria and Schagdarsurengin, Undraga and Kehlen, Astrid and Garbe, James C. and Stampfer, Martha R. and Dammann, Reinhard}, citeulike-article-id = {6056390}, citeulike-linkout-0 = {http://dx.doi.org/10.1128/MCB.25.10.3923-3933.2005}, citeulike-linkout-1 = {http://mcb.asm.org/content/25/10/3923.abstract}, citeulike-linkout-2 = {http://mcb.asm.org/content/25/10/3923.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/15870267}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=15870267}, day = {15}, doi = {10.1128/MCB.25.10.3923-3933.2005}, journal = {Mol. Cell. Biol.}, keywords = {chf, chip, rassf1a}, month = {May}, number = {10}, pages = {3923--3933}, posted-at = {2009-11-02 13:51:10}, priority = {0}, title = {Chromatin Inactivation Precedes De Novo DNA Methylation during the Progressive Epigenetic Silencing of the RASSF1A Promoter}, url = {http://dx.doi.org/10.1128/MCB.25.10.3923-3933.2005}, volume = {25}, year = {2005} }

TY - JOUR ID - citeulike:6056390 L3 - citeulike-article-id:6056390 N2 - Epigenetic inactivation of the RASSF1A tumor suppressor by CpG island methylation was frequently detected in cancer. However, the mechanisms of this aberrant DNA methylation are unknown. In the RASSF1A promoter, we characterized four Sp1 sites, which are frequently methylated in cancer. We examined the functional relationship between DNA methylation, histone modification, Sp1 binding, and RASSF1A expression in proliferating human mammary epithelial cells. With increasing passages, the transcription of RASSF1A was dramatically silenced. This inactivation was associated with deacetylation and lysine 9 trimethylation of histone H3 and an impaired binding of Sp1 at the RASSF1A promoter. In mammary epithelial cells that had overcome a stress-associated senescence barrier, a spreading of DNA methylation in the CpG island promoter was observed. When the RASSF1A-silenced cells were treated with inhibitors of DNA methyltransferase and histone deacetylase, binding of Sp1 and expression of RASSF1A reoccurred. In summary, we observed that histone H3 deacetylation and H3 lysine 9 trimethylation occur in the same time window as gene inactivation and precede DNA methylation. Our data suggest that in epithelial cells, histone inactivation may trigger de novo DNA methylation of the RASSF1A promoter and this system may serve as a model for CpG island inactivation of tumor suppressor genes. 10.1128/MCB.25.10.3923-3933.2005 IS - 10 JF - Mol. Cell. Biol. EP - 3933 TI - Chromatin Inactivation Precedes De Novo DNA Methylation during the Progressive Epigenetic Silencing of the RASSF1A Promoter VL - 25 SP - 3923 KW - chf KW - chip KW - rassf1a AU - Strunnikova, Maria AU - Schagdarsurengin, Undraga AU - Kehlen, Astrid AU - Garbe, James AU - Stampfer, Martha AU - Dammann, Reinhard PY - 2005/05/15/ UR - http://dx.doi.org/10.1128/MCB.25.10.3923-3933.2005 ER -