Marisa Bartolomei, Ph.D.

The work in my laboratory focuses on elucidating the mechanisms governing genomic imprinting in mammals. Imprinted genes number in the hundreds, are largely located in domains and are expressed from a single parental allele. This monoallelic gene expression pattern is set in the gametes and maintained during development using epigenetic mechanisms such as DNA methylation and posttranslational histone modifications. Genomic imprinting is an excellent model for studying epigenetic gene regulation during mammalian development. We have used mouse models with mutations in cis-acting regulatory sequences and trans-acting epigenetic factors to study imprinted gene regulation, including examining tissue-specific effects and higher order chromatin structure and architecture. Historically we conducted in depth analyses of the H19–Igf2 imprinted locus but have more recently expanded to Grb10–Ddc1 locus to reveal cis-acting regulatory elements. For elucidating establishment and maintenance of imprinted gene expression we have studied most of the imprinted loci and incorporated genome-wide approaches and mutations in the DNA methylation machinery. Specifically, we have studied the role of oxidase TET1 in reprogramming of iPSCs and genomic imprints, more recently expanding to study reprogramming of the male germline using a series of Tet1 mutant mice. We have also studied X inactivation in many of these model systems.

Additionally, we use mouse models to study the epigenetic consequences of environmental perturbations such as in utero exposure to endocrine disrupting compounds (EDCs) and Assisted Reproductive Technologies (ART). With respect to EDCs, we have used a mouse model to show that BPA exerts an abnormal metabolic, skeletal health and behavior phenotypes, largely observed in males. In these models we have focused on placenta as well as fetal and postnatal phenotypes. For the ART mouse model, we have studied the long-term outcomes of procedures used in assisted reproduction and have observed sex-specific metabolic and cardiovascular phenotypes and behavioral perturbations as mice age. Moreover, we have shown that embryo culture in the most significant procedure with respect to conferring abnormal DNA methylation profiles in ART-conceived offspring. Finally, we have employed high throughput technologies to study DNA methylation, transcription, chromatin structure and proteomics in a variety of cell types.