Yevgeniy Shakirov, PhD
Our research interests include several interconnected projects that focus on the interface of fundamental and applied biology and medicine. We investigate key genetic determinants of cellular homeostasis, including predisposition to aging-associated diseases, response to stress and identification of novel plant metabolites with antimicrobial activity. Students interested in modern approaches of molecular cell biology, genetics, genomics, and biochemistry are welcome to inquire about research opportunities.
Molecular mechanisms of telomere maintenance
The maintenance of telomeres is a fundamental and evolutionarily conserved cellular process, with important implications for human health, premature aging, and degenerative stem cell diseases. In humans, telomere length is likely under strong stabilizing selection, since accelerated telomere shortening is linked to age-related diseases and overly long telomeres are linked to cancer. Hence, deregulation of proper telomere length homeostasis is emerging as a strong determinant of human disease.
We utilize genomic, genetic and transgenic approaches to identify genes that control telomere length set point in the model plant Arabidopsis thaliana with the broader goal of integrating these results with other eukaryotic systems. Recently, using a system genetics approach combined with a mutation knock-out analyses we uncovered NOP2A, a ribosomal RNA methyltransferase with major roles in cellular proliferation. Loss-of-function studies establish NOP2A and its interacting RPL5 genes as novel positive trans-regulators of telomere length set point in plants and implicate ribosome biogenesis and cell proliferation pathways as major regulators of telomere biology across eukaryotic evolution. Further deciphering evolutionarily conserved mechanisms regulating telomere length in plants and other eukaryotes may provide novel insights into the molecular basis for different rates of aging and predisposition to telomere-associated stem cell, cancer, and age-related diseases in humans.
Discovery and comparative analysis of novel antimicrobial compounds from model mosses.
One of the most promising approaches in the fight against pathogens is the use of secondary plant metabolites with potent antimicrobial activity. Towards this goal, the use of secondary metabolites from bryophytes – mosses and liverworts – can be of particular value, as they often possess unique qualities not present in metabolites from other plant lineages. We aim to identify and characterize the whole spectrum of secondary metabolites of model bryophytes and elucidate their antimicrobial potential based on growth inhibition of pathogenic bacteria and fungi in vitro and in vivo. This approach will allow us to combine the facile genetics and genomic tools of model bryophytes with advanced biochemical and proteomic analysis methods to discover and characterize the wide range of biologically active secondary metabolites from this group of ancient but previously not well-characterized plants. Novel metabolites with antibacterial and antifungal activities can then be developed into new biotechnological tools to fight plant and human pathogens.
The connection between telomere plasticity, pleiotropy and organismal fitness
Telomere dynamics is a useful parameter in the context of ecology and evolution research as a readout of organismal response to environmental stress. For example, in humans with predisposition to premature telomere shortening, environmental factors can have an additional negative impact on telomere dynamics. Overall, telomere dynamics represents a fine compromise between potential positive gains in organismal survival and associated negative energy costs.
In this project, we apply a multifaceted approach to further extend our current understanding of the evolutionary and ecological bases of the interplay between telomere biology and environment. Specifically, we use reference Arabidopsis genotypes and various mutant lines in this background to study the effects of environmental stress (i.e. high temperature and drought, pathogen attack) and analyze corresponding changes in telomere dynamics and fitness parameters. Our current data indicate that the state of telomere biology can have important implications on overall plant physiology and fitness. Overall, these experiments address several fundamental questions on telomere biology, which will be applicable to not only plants but also to other eukaryotes, including humans.