Bluma Lesch

Scholar: 2019

Awarded Institution
Assistant Professor
Yale University
Genetics

Website

Research Interests

Evolution and Molecular Control of Gene Regulation in the Animal Germ Line 

When we think about the mechanisms of inheritance, we think of DNA carrying information from one generation to the next.  In fact, not all DNA molecules have this privilege: only DNA carried by specialized cells, the germ cells (sperm, eggs, and their developmental precursors), is actually passed between generations.  Germ cells are therefore uniquely responsible for ensuring fidelity of inheritance in a species.  In particular, the mechanisms that germ cells use to regulate and protect their DNA genome are critical for both individual fitness and species survival.  These mechanisms depend on chromatin, the combination of RNA and protein that packages the DNA genome.  My research focuses on understanding how chromatin is regulated in animal germ cells, and discovering how germ cells use chromatin to ensure both correct development of offspring in the next generation and endurance of the species over millions of generations.  

We are using a combination of evolutionary functional genomics and molecular genetics to approach this problem.  I previously showed that a particular type of chromatin, called epigenetic poising, is a fundamental feature of the mammalian germ line.  Epigenetic poising is associated with the ability of a precursor cell to differentiate into many different mature cell types.  I found that poising is conserved in developing sperm throughout evolution of the mammalian lineage, and evolves along with gene networks that control development of the embryo.  We are now testing the hypothesis that epigenetic poising in germ cells is important for preparing developmental genes to be used in the embryo after fertilization; if so, these findings will imply that non-genetic information from one generation can be passed on to offspring, a major change in the way we think about inheritance.   

To define the evolutionary history of poising and of other types of chromatin in animal germ cells, we are comparing chromatin state across the genome in male germ cells of many different species.  In addition, we are experimentally testing the biological significance of species differences in chromatin by manipulating it at particular sites in one species to resemble the chromatin state of another species at the equivalent site.  In addition, we are using genetic screens to identify new chromatin regulators in mammalian germ cells.  From our position at the intersection of developmental biology, evolution, reproduction, and genetics, our research will uncover new knowledge about the fundamental mechanisms of heredity and about how their failure can contribute to disease.