Grant: Discovery Grants Program - Individual

Bone marrow of humans and other animals contains stem cells that can become each of the various cell types of the immune system. This process, called differentiation, creates specific types of immune cells and requires changes in gene expression that are initiated by cell signaling events. Genes important for the flexible nature of the stem cell are turned off, while genes important to the mature immune cell are activated. These changes in gene expression involve stable structural changes to chromatin or DNA in a process called epigenetic gene regulation. Specific genes are turned off by packaging them very tightly so that they are inaccessible within the chromatin, while others are turned on by packaging more loosely to ease access. The processes of histone acetylation and DNA methylation are major contributors.Mast cells are an immune cell type that plays important roles in defense, but we do not fully understand how they differentiate from stem cells. One type of signaling that we know is important for the differentiation of mast cells is the mitogen-activated protein kinase (MAPK) pathway. MAPK signaling is connected to epigenetic changes during the differentiation of other cell types and we know that it is activated and important for mast cell differentiation. While some epigenetic changes have been found in mast cell differentiation, the signaling that controls it is unknown. The link between these events represents a major gap in our understanding, and highlights the novelty of my proposed research. My research team has identified the activation of several epigenetic enzymes in differentiating mast cells. We hypothesize that MAPK signals contribute to activation of epigenetic enzymes which cause mast cell genes to be turned on and stem cell genes to be turned off during differentiation. To determine the role of the MAPK signaling in mast cell differentiation epigenetics, we will conduct experiments to meet the following 3 objectives: 1) Determine the importance of MAPK signaling in histone acetylation during mast cell differentiation. 2) Assess the role of MAPK signaling in DNA methylation during mast cell differentiation. 3) Examine the significance of MAPK proteins entering the nucleus during mast cell differentiation and activation. Expected significance: The overall objective of the proposed research is to improve our understanding of how MAPK proteins regulate gene expression within the nucleus during mast cell differentiation. MAPK signaling is highly conserved and important in a wide variety cell functions, including growth, differentiation, development, response to stress, and cell death. Given this breadth of functional roles, the results obtained could have broad biological applications. This work will enhance our perspective on the connections between cell signaling mechanisms and epigenetic gene regulation, an emerging area of research in the natural sciences.