McKay receives NIH "Maximizing Investigators' Research Award"

Daniel J. McKay, PhD, assistant professor, Biology and Genetics and Integrative Program for Biological and Genome Studies (iBGS), has received a 5-year $1.25 million MIRA grant for his project titled “Genetic and Epigenetic Mechanisms of Developmental Gene Regulation."

McKay's lab studies gene regulation in development, with the goal of understanding how distinct cell fates are specified and maintained over time. In particular, they study the DNA switches that turn genes on and off. Proper specification of cell fates during development depends on activation of these switches, called enhancers, in the right time and place. Defects in the pathways that control enhancer activity lead to the gene expression changes that underlie nearly all diseases. However, the mechanisms controlling how and when enhancers are used remain incompletely understood.

By default, enhancers are inaccessible to the proteins that control their activity. In order to turn genes on, the packaging around enhancers, termed chromatin, must be opened up, thereby making enhancer DNA accessible for use. Equally important, but less well understood, is the process by which open enhancers are returned to a closed, quiescent state. Using the fruit fly Drosophila melanogaster, the proposed research will study how enhancers are opened and closed during development by identifying the key regulators of enhancer accessibility and the protein machines with which they work.

Proper specification and maintenance of cell fates also depends on memory of decisions made earlier in development. Maintaining cell identities over time is not dependent on changes in the DNA sequence. Instead, "epigenetic" mechanisms propagate information on cell identity by maintaining select sets of genes in either the on or off state. Chemical modifications of histone proteins, which package and organize the genome within cells, are thought to play a central role in epigenetic gene regulation. However, identifying which histone modifications are required for gene regulation, and defining the mechanisms through which they function in the maintenance of cell identity, remains a longstanding research challenge. The proposed research will investigate how histone modifications surrounding enhancers affects enhancer activity in different tissues and over developmental time.

The MIRA (R35) award mechanism provides support for the research in an investigator's laboratory that falls within the mission of National Institute of General Medical Sciences (NIGMS). The goal of MIRA is to increase the efficiency of NIGMS funding by providing investigators with greater stability and flexibility, thereby enhancing scientific productivity and the chances for important breakthroughs. The program will also help distribute funding more widely among the nation's highly talented and promising investigators.

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