Characterization of aberrant DNA methylation changes in fertility and paragangliomas

Our work focussed on how germ cell DNA is packaged and if it is poised by distinctive chromatin to influence embryo development. Finally, is misregulation of that poising a common theme observed in infertility and cancer? We profiled the epigenome in mature human sperm and found that packaging in mature sperm revealed the presence of two programs - a future program, involved in guiding embryo development and a past program, involved in spermatogenesis (Chapter 2). Next, the clearest place a chromatin problem can manifest is in infertility. We asked if the DNA methylation status of seven imprinted regions can serve as a diagnostic to inform two groups of infertile patients about the risk of their offspring developing a disorder. Although our results did not provide a causal link for the trans-generational inheritance of DNA methylation defects leading to imprinting disease, it showed a strong correlation between infertility in males and aberrations of DNA methylation at select imprinted loci (Chapter 3). Taken together, our data suggests that germ cell chromatin plays a significant role in early embryonic development and infertility. Finally, we investigated how defects in a metabolic enzyme, succinate dehydrogenase (SDH) can have an impact on chromatin packaging and transcriptome of paragangliomas. We also queried the epigenetic status of paragangliomas lacking mutations in SDH. We compared our two PGL subclasses to a progenitor cell type, neural crest cells (NCCs). Strikingly, we found that both subclasses of PGLs are phenotypically very similar. Furthermore, they share the majority of regions that gain and lose DNA methylation compared to neural crest cells. Whole exome sequencing of both PGL subclasses shows iv mutations in many epigenetic modifier genes and hence we speculate that in PGLs lacking SDH mutations, epigenetic enzymes may harbor mutations that could phenocopy the misregulation in SDH deficient tumors (Chapter 4). Together, we hope that by querying the epigenetic status in a normal system and comparing these findings to perturbed systems, we have gained more insight into the role of epigenetic misregulation in infertility and cancer.