Cancer has been described as a disease of the genome, and epigenetic regulation plays an important role. In cancer cells, normal DNA methylation and repressive chromatin modifications are lost from some repetitive sequences including transposable elements (TEs). Reactivated TEs cause new mutations as well as affect the expression of neighboring genes. However, these findings are based on a limited number of examples from single gene studies. In order to understand how changes in TE regulation lead to changes in gene expression on a global scale, a genomics approach is necessary. The model plant Arabidopsis thaliana has been sequenced and has a comprehensive collection of mutants in epigenetic regulation. I propose to use an innovative whole chromosome tiling microarray to investigate changes in TE regulation that lead to variations in gene expression in Arabidopsis. This research will determine the extent to which epigenetically reactivated TEs mediate expression changes genome-wide, leading to epigenetic alterations such as those found in cancer. First wild-type, and then mutants with reactivated TEs will be assayed by microarray to determine the extent of transposable element influence on the genome by measuring gene expression levels, DNA methylation, small RNAs and histone modifications for an entire chromosome. Additionally, screening for TE reactivation and excision will identify new genes involved in silencing TEs. Finally, each mutation will be tested to determine what factors are responsible for the heritability of the reactivated TEs. By understanding the relationship between the epigenetic regulation of TEs and gene regulation, this research will further the understanding of the role of TEs in oncogenesis and cancer progression. Additionally, by defining the factors necessary for the reestablishment of the native silenced state of TEs, this research will suggest new possible approaches for cancer treatment. ? ? Relevance to public health: Roughly half of the DNA in each human cell is composed of repetitive or 'junk' DNA that is normally repressed and does not contribute to the formation of proteins from genes. However, the natural repression system occasionally fails, leading to the repetitive DNA erroneously influencing individual neighboring genes. The overall extent to which the natural repression system and repetitive DNA contribute to gene activity and cancer formation will be investigated in this research. ? ? ?
| Slotkin, R Keith; Vaughn, Matthew; Borges, Filipe et al. (2009) Epigenetic reprogramming and small RNA silencing of transposable elements in pollen. Cell 136:461-72 |
| Martienssen, R A; Kloc, A; Slotkin, R K et al. (2008) Epigenetic inheritance and reprogramming in plants and fission yeast. Cold Spring Harb Symp Quant Biol 73:265-71 |
