Post Doctoral Researcher

The Modzelewski Lab (TheModzLab) at the University of Pennsylvania Department of Biomedical Sciences School of Veterinary Medicine is recruiting 2 postdoctoral researchers or research associates to join an exciting new NIH-NICHD funded project. Our work focuses on the exciting and emerging role of retrotransposons in early development and disease. We investigate the impact retrotransposons have on fertility and preimplantation development in mice along with comparative biology studies using various placental mammalian species to learn about human health and reproduction.

The lab has two major but linked focuses: Developmental Biology and Genome Editing.

Nearly half of all mammalian genomes originate from ancient retroviral integrations. While silenced in nearly all cells, retrotransposon reactivation is a well-known phenomenon in preimplantation embryos and the germline. Reactivation is also observed during epigenetic breakdown that occurs in aging, disease and cancer. Some retrotransposons retain regulatory and structural features that can influence nearby genes. In the embryo, these events are transient and span less than a cell cycle. We found many examples of enhancers, repressors and chromatin boundaries. A subset of these events splice with nearby protein coding genes, generating conserved embryo-specific splicing isoforms called "chimeric transcripts" that form hundreds of novel promoters, exons and polyadenylation sites. Deletions made in the lab have led to defects in cellular homeostasis, infertility, embryonic and maternal lethality and improper implantation that resembles human pregnancy complications. Recently published work discovered the first essential retrotransposon in mammals (Cell 2021). Importantly, retrotransposons are also observed to reactivate in cases of epigenetic breakdown, such as aging, disease and aggressive cancers. This highly collaborative project adapts proteomics, genetics, bioinformatics and CRISPR/Cas9 editing to reveal this overlooked but essential form of retrotransposons-based regulation in development, fertility, and disease.

To aid in these investigations, we are also interested in technology development. As no current cell culture system faithfully represents preimplantation development, most of the research at this stage must be done directly in the embryo and animal models. Even with the advent of CRISPR/Cas9 gene editing, generating mouse models is cost prohibitive and largely inaccessible. Therefore, I developed a highly efficient electroporation-based editing technique called CRISPR-EZ (CRISPR Electroporation of Zygotes) that is 3-4x more efficient than the gold standard of microinjection, inexpensive, works in all species tested, and can be mastered quickly, making this technology uniquely accessible to many academic labs (JBC 2016, Nature Protocols 2018, JOVE 2022). While small insertions and deletion strategies have been highly optimized, there is still room to improve in larger insertions, deletion, and sophisticated model designs. Current efforts include the use of AAV, CRISPRa/i (activation/interference), humanized models to study conserved developmental regulatory networks.

Qualifications:
• PhD degree in biology, genetics, genomics, biomedical sciences as well as bioengineering,
biostatistics, computational, etc.
• We encourage applicants with experience in developmental biology and/or non-coding RNA
• Previous mouse handling experience and embryo manipulation is a plus but not essential.
• Ideal candidate should enjoy working with others, be highly motivated and passionate about biology,
development, reproduction and apply this knowledge to human health and disease.

Application Documents:
• CV or Resume (with contact information for 2-3 references)
• Cover Letter detailing interest and experience

For more information, please visit our website: www.TheModzLab.org

Interested applicants are invited to submit their application documents directly to Dr. Modzelewski at https://tinyurl.com/6my96vry





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