LSD1 reprograms epigenetic memory to enable changes in cell fate

Emory University, Atlanta GA

Investigators

Abstract

Nontechnical explanation In 2001, Dr. David Allis proposed that small chemical modifications in the packaging of DNA could form a code that affects the expression of genes. Since then, an intense effort has been underway to understand what these different modifications do and how they affect the biology of organisms. Previously my lab provided evidence in worms suggesting that these modifications can be stably inherited from cell to cell as cells replicate themselves. These experiments will determine what happens to this information as genes are passed from parents to offspring in mammals. In addition, this research will determine whether or not the information contained in the packaging of DNA can influence the information encoded in the DNA itself. By understanding these basic biological mechanisms, this work has the potential to shed light on the cause of a broad range of diseases, from birth defects to autism. All of the experiments will be carried out in partnership with undergraduates from the nearby Oglethorpe University, under the guidance of Oglethorpe professor Dr. Karen Schmeichel. These students, many of whom are minorities and/or first in their family to go to college, have no access to research using mice, the preeminent human model. Therefore, providing these students with the opportunity to participate in this research has the potential to profoundly impact their understanding of science and scientific research. Technical description Two of the most fundamental parts of the existence of multicellular organisms are (1) the ability of cells to maintain their cell fate, and (2) how cells undergo changes in cell fate during key developmental transitions. To accomplish this, cells must be able to (A) faithfully transmit patterns of gene expression through mitosis and (B) change transcriptional patterns during developmental transitions. However, the mechanisms that control these processes are currently unknown. To investigate these mechanisms we will use a mouse model of the histone demethylase LSD1/KDM1a to determine the function of this enzyme during (1) the gamete-to-embryo transition and (2) in testis stem cells. Through these experiments, we will (A) determine whether histone methylation can function as a transcriptional memory in mammals, (B) investigate the relationship between histone methylation and DNA methylation and (C) determine the function of LSD1 in regulating cell fate. By providing a potential paradigm shift in our understanding of how histone methylation functions to maintain cell fates and how this histone methylation is regulated during cell fate transitions, this work has the potential to highly impact our understanding and treatment of a broad spectrum of diseases, from birth defects to autism.