Epigenome Profiling Analysis During Breast Cancer And Kidney Cancer Development

Epigenetic modifications mainly contain DNA methylation and histone modifications.Epigenetic modification alteration can affect chromatin organization and regulate gene expression.H3K9 methylation mainly locate within heterochromatin region,maintain chromatin stability,repress transposon activity and suppress gene expressio.H3K9 methylation alteration will change chromatin structure,and related to cell differenciation and carcinogenesis.Breast cancer is the most popular cancer in women.Tumor suppress gene mutation and estrogen stimulation are the common factors resulted in breast cancer,except many epigenetic modification enzymes were found mutant in breast cancer and results in gene expression disorder.We transfered large T antigen,TERT and RASV12 three plasmids to breast epithelia cells and successfully generated breast cancer cells.We found that H3K9 methylation decrease during breast cancer transformation.H3K9me2 is widely distributed in the genome and mainly in the form of LOCKs.During breast cancer development many cancer related genes located with H3K9me2 decrease LOCKs boundary region were activated.We found that histone demethylase KDM3A was upregulated in breast cancer.KDM3A can remove H3K9me2 modification in many oncogenes and activate those genes.We thought KDM3A is an oncogene in breast cancer.Our findings provide new targets for breast cancer diagnosis and treatment.H3K9me3 is the marker of heterochromatin,H3K9me3 decrease will influence genome stability,promote DNA damage and mutation.H3K9me3 peaks can be divided into different partial according to length.H3K9me3 larger peaks were conserved in four cell types,while H3K9me3 small peaks dynamic alter during breast cancer transformation.Genes located within H3K9me3 small peaks enriched in transcriptional regulation.H3K36me3 mainly distributed on the genebody of transcription activited genes,related to mRNA alternative splicing,DNA mismatch repair and homologous recombination.In the human genome SETD2 is the main H3K36me3 methyl transferase.SETD2 is highly mutated in many kinds of cancer,such as in clear cell renal cancer SETD2 was often deleted,SETD2 mutation happened in prostate cancer.SETD2 was supposed to be a tumor suppressor gene.Studying intracellular SETD2 dynamic regulation is very important.By using yeast two hybrid screening we found SPOP can interact with SETD2 and functional as E3 ligase.Our transcriptome and H3K36me3 epigenome data indicated that,in kidney cancer SPOP can change H3K36me3 modification by regulating SETD2 stability specificlly,and then affected gene alternative splicing patterns.