The Modzelewski Lab (“Modz Lab”) is interested in the phenomenon of Retrotransposon Reactivation in development and disease. The genome goes through great lengths to suppress the activity of retrotransposons by evolving epigenetics mechanisms to suppress their parasitic lifecycle until they are mutated over millions of years. Now making up nearly 50% of the human genome, retrotransposons have recently emerged as important features of Normal Biology across all mammalian species. For brief instances during preimplantation (and likely germline) development, epigenetic surveillance mechanisms are paradoxically relaxed and allow retrotransposons to reactivate for unknown reasons.
Using CRISPR/Cas9 based electroporation technology developed in our lab to manipulate mammalian zygotes (CRISPR-EZ), we have generated Retrotransposon KnockOut (KO) mouse models, essentially restoring the genome to a “pre-integration” state”, to study distinct mechanisms that operate in the early embryo. Our work has shown at least one retrotransposon mechanism is essential for development in the mouse through control of a highly conserved cell cycle mechanism to regulate embryo implantation. Additional KO mice reveal roles in fertilization, global translation synthesis, response to metabolic stress and others. This is only the tip of the iceberg in terms of what Retrotransposons are capable of.
Developmental retrotransposons reactivation appears essential and intentional, and thus we apply these findings to study the unintentional retrotransposon reactivations that occur during epigenetic breakdown associated with aging, disease, and cancer. Retrotransposons have rewired regulatory networks and provided raw material for genetic innovation through co-option of innate regulatory sequences and repurposing (domestication) of proteins that were once used to invade our genomes. These events were critical in shaping evolution and are responsible for essential biological breakthroughs like the placenta, VDJ recombination, memory plasticity and much more.
Study mammalian preimplantation embryos to understand the biological importance of retrotransposon reactivation.
Phenotypical analysis and mechanistic understanding of retrotransposon knockout (KO) mouse models.
Develop Humanized mouse models to study Human specific retrotransposons.
Probe embryos, germline, mouse and human stem cells to understand retrotransposon regulation and function.
Explore retrotransposon reactivation consequences outside of the embryo, where epigenetic breakdown occurs, such as aging, disease and cancer.
Improvements to genome editing technologies (CRISPR-EZ) in mammalian embryos for longer inserts, higher efficiency and lower costs.
Andrew J Modzelewski, Johnny Gan Chong, Ting Wang, Lin He Mammalian genome innovation through transposon domestication Nature Cell Biology 24: 1332-1340, 2022.Diallo, C. K., Modzelewski, A. J Efficient Genome Editing of Mice by CRISPR Electroporation of Zygotes. J. Vis. Exp (JOVE) 190: e64302, 2022.Rosas-Canyelles, E., Modzelewski, A. J., Geldert, A., He, L., Herr, A. E. Multimodal detection of protein isoforms and nucleic acids from mouse pre-implantation embryos Nature Protocols 16: 1062-1088, 2021.Modzelewski, A. J., Shao, W., Chen, J., Lee, A., Qi, X., Noon, M., Tjokro, K., Sales, G., Biton, A., Anand, A., Speed, T. P., Xuan, Z., Wang, T., Risso, D., He, L. A mouse-specific retrotransposon drives a conserved Cdk2ap1 isoform essential for development Cell 184: 5541-5558.e22, 2021.Tsitsiklis, A., Bangs, D. J., Lutes, L. K., Chan, S. W., Geiger, K. M., Modzelewski, A. J., Labarta-Bajo, L., Wang, Y., Zuniga, E. I., Dai, S., Robey, E. A. An unusual MHC molecule generates protective CD8+ T cell responses to chronic infection Frontiers in Immunology 11: 1464, 2020.Rosas-Canyelles, E., Modzelewski, A. J., Geldert, A., He, L., Herr, A. E. Assessing heterogeneity among single embryos and single blastomeres using open microfluidic design Sci Adv 6: eaay1751, 2020.Modzelewski, A. J., Chen, S., Willis, B. J., Lloyd, K. C. K., Wood, J. A., He, L. Efficient mouse genome engineering by CRISPR-EZ technology Nature Protocols 13: 1253-1274, 2018.Hilz, S., Fogarty, E. A., Modzelewski, A. J., Cohen, P. E., Grimson, A. Transcriptome profiling of the developing male germ line identifies the miR-29 family as a global regulator during meiosis RNA Biology 14: 219-235, 2017.Sun, X., Brieno-Enriquez, M. A., Cornelius, A., Modzelewski, A. J., Maley, T. T., Campbell-Peterson, K. M., Holloway, J. K., Cohen, P. E. FancJ (Brip1) loss-of-function allele results in spermatogonial cell depletion during embryogenesis and altered processing of crossover sites during meiotic prophase I in mice Chromosoma 125: 237-52, 2016.Chen, S., Lee, B., Lee, A. Y., Modzelewski, A. J., He, L. Highly efficient mouse genome editing by CRISPR ribonucleoprotein electroporation of zygotes Journal of Biological Chemistry 291: 14457-67, 2016.