In normal cells, DNA methylation is rare in promoter-associated CpG islands but important to X-inactivation, genomic imprinting and repression of repetitive elements. During tumorigenesis hundreds to thousands of genes gain methylation in promoter-associated CpG islands, affecting many pathways including tumor- suppressor pathways. The causes of this massive switch in DNA methylation remain mysterious. Interestingly, some genes are refractory to abnormal de-novo methylation in cancer while others are frequently targeted. Deciphering the differences between CpG islands sensitive or resistant to aberrant methylation will lead to a better understanding of the cellular factors that modulate cancer-specific DNA hypermethylation. Based on preliminary data, our central hypothesis to explain this difference is that an interplay between local sequence features (repeat elements, recognition sites for DNA binding proteins) and baseline chromatin states (histone modifications) related to developmental transcription programs modulates CpG island methylation in cancer. To test this hypothesis, we propose the following specific aims: (1) Identify baseline genetic and epigenetic features which segregate genes with propensity to become de-novo methylated in cancer from genes protected from de-novo methylation; and (2) use cellular models of DNA methylation induction to validate the individual and cooperative action of candidate genetic and epigenetic features.
In specific aim 1, we propose (a) to measure the propensity of promoter-associated CpG islands to DNA hypermethylation in myeloid leukemia and colorectal carcinomas) and (b) to identify the genomic (transcription factor binding sites, retrotransposons, short direct repeats) and epigenomic (histone modifications in normal cells) factors that distinguish methylation-prone versus methylation-resistant CpG islands. Significant features will be entered in a mathematical model to reveal individual and cooperative activity in modulating methylation in cancer, and the model will be validated in other samples and tumor types. The most significant features and known factors associated with differential predisposition to DNA methylation (the transcription factor Sp1, LINE/SINE retrotransposons and the insulator proteins CTCF, USF1/2 and VEZF1) will be tested in specific aim 2. For this testing we will use a series of cellular models developed in our laboratory where engineered transgenes can be inserted in specific genomic loci, and later on moved in and out of repressive contexts due to the presence of tetracycline-induced repressors. We expect that the successful development of our research will bring novel insights in how abnormal DNA methylation is targeted to specific genes while sparing others, and will also result in the identification of multiple targets for epigenetic-based therapies.
Alteration of the pattern of DNA methylation is observed in a large fraction of human cancers, and therapies targeting this epigenetic mark have proved effective in the treatment of several human neoplasias. How cancer cells acquire an altered DNA methylation profile is not fully understood, and we have found evidence that specific genes have an inherent predisposition to become methylated. In this study, we will perform a comprehensive evaluation of the genomic features associated with predisposition and resistance to DNA methylation, and we expect to derive a model that explains aberrant hypermethylation events observed in cancer.
| Kelly, Andrew D; Madzo, Jozef; Madireddi, Priyanka et al. (2018) Demethylator phenotypes in acute myeloid leukemia. Leukemia 32:2178-2188 |
| Good, Charly Ryan; Panjarian, Shoghag; Kelly, Andrew D et al. (2018) TET1-Mediated Hypomethylation Activates Oncogenic Signaling in Triple-Negative Breast Cancer. Cancer Res 78:4126-4137 |
| Zhang, Hanghang; Pandey, Somnath; Travers, Meghan et al. (2018) Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer. Cell 175:1244-1258.e26 |
| Kelly, A D; Kroeger, H; Yamazaki, J et al. (2017) A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome. Leukemia 31:2011-2019 |
| Sato, Takahiro; Cesaroni, Matteo; Chung, Woonbok et al. (2017) Transcriptional Selectivity of Epigenetic Therapy in Cancer. Cancer Res 77:470-481 |
| Werner, Rachael J; Kelly, Andrew D; Issa, Jean-Pierre J (2017) Epigenetics and Precision Oncology. Cancer J 23:262-269 |
| Issa, Jean-Pierre J (2017) Introduction: Cancer as an Epigenetic Disease. Cancer J 23:255-256 |
| Good, Charly R; Madzo, Jozef; Patel, Bela et al. (2017) A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer. Nucleic Acids Res 45:8269-8281 |
| Maegawa, Shinji; Lu, Yue; Tahara, Tomomitsu et al. (2017) Caloric restriction delays age-related methylation drift. Nat Commun 8:539 |
| Raynal, Noël J-M; Da Costa, Elodie M; Lee, Justin T et al. (2017) Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome. Mol Cancer Ther 16:397-407 |
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