Research

Sex differences in germ cells are believed to be epigenetically regulated, as distinct differences in DNA methylation and histone modifications have been found in germ cells during sex determination. We are studying epigenetic regulation of germ cell development, including epigenetic reprogramming of primordial germ cells (PGCs), using olvasGFP medaka as a model organism. Our research shows that medaka PGCs undergo epigenetic reprogramming (regarding DNA methylation dynamics) similarly to mammals. We are investigating the role of the Y chromosome in the epigenetic reprogramming of germ cells, as fish without the Y chromosome lack this pattern of epigenetic reprogramming.

Programming of parental methylomes (genomewide DNA methylation profile) is essential for embryo development and of primordial germ cells (PGCs) for gender-specific germ cell development from its pluripotent state. Our results suggest that medaka reprogram their methylomes in early embryos and PGCs the same way mammals do. This makes medaka fish an ideal organismal model for studying epigenetic regulation of transcription in health and disease and inheritance of environmentally induced epigenetic signals.

In model organisms, mate selection and mating behaviors have been found to be affected by developmental exposure to environmental estrogenic or anti-androgenic chemicals, suggesting that current environmental levels of chemicals could be affecting the health and behavior of the exposed organisms. Our team is striving to understand the epigenetic basis for brain sexual dimorphism, environmentally induced sex-specific behaviors, and neuroendocrine disruption.

The window of early embryonic development is susceptible to environmental chemical stressors. Exposures during gonadal sex determination may lead to reproductive defects in adulthood. These effects can be transgenerationally transmitted to subsequent generations via the germline (sperm and eggs).  Transgenerational effects appear in individuals, not because of direct exposure but due to ancestral exposure, and have been thought to be contributing to declining reproductive fitness and the emergence of endangered species in natural populations. We are studying molecular alterations occurring during the transgenerational inheritance of phenotypes to identify chemical and phenotype-specific biomarkers associated with adverse reproductive outcomes using medaka fish (d-rR medaka, Oryzias latipes) as a model organism. We anticipate the biomarkers to be reliably predictive of the history of exposure and associated transgenerational phenotypes.

Gene-environment interactions can lead to the emergence of phenotypes. Environmental stressors are able to induce epigenetic changes (chemical modifications on DNA structure) that are mitotically (or meiotically) stable. Environmental stressor-induced chemical modifications, such as DNA methylation or histone modifications, may or may not survive epigenetic reprogramming events that occur during the early cleavage stage of an embryo or during the re-specification of primordial germ cells (PGCs) at the time of sex determination. We hypothesize that the epigenetic modifications that survive reprogramming serve as epigenetic memories and that these memories are associated with adverse health outcomes. 

Our research is focused on unraveling epigenetic memories established by estrogenic chemicals that humans and aquatic wildlife are exposed to. We take in vitro cell culture, in vivo animal models, next-generation high throughput miRNA/RNA/methylome sequencing and histone profiling, and bioinformatic approaches to dissect the molecular underpinning of environmentally induced health effects across three generations using medaka and mice as model organisms. We anticipate finding permanent epigenetic memories that alter fine-tuned developmental transcriptional wiring leading to altered health conditions.