DOT1L and H3K79 methylation in fibrosis.

Fibrosis is a process characterized by excessive deposition of connective tissue components such as collagen fibers in tissues and organs. Fibrosis impairs organ structure and function and is an important factor in various diseases. Systemic sclerosis is a severe chronic autoimmune connective tissue disease. Its outcome is largely determined by severe fibrosis affecting the skin and internal organs such as the lungs. Currently, no specific and successful treatment is available to prevent this severe complication of SSc. The fibrotic process is regulated by different growth factors such as transforming growth factor-beta and Wnt molecules. In a search for therapeutic targets, mechanisms regulating gene transcription are increasingly identified. In this project we focus on DOT1L, an enzyme that catalyses methylation of a specific lysine amino-acid in histone 3. This chemical modification of a protein in the cell nucleus increases gene transcription and cell activity. We will use mouse and cell culture or tissue models to decipher the molecular interactions of DOT1L and its effect on fibrosis. We hypothesize that loss or inhibition of DOT1L will limit the fibrotic response. Our experimental approach will not only look at cell and animal model systems but will also validate these results using cells and tissue samples from patients, thereby linking laboratory conditions with the clinic.

Keywords:fibrosis, DOT1L, methylation, H3K79

Disciplines:Orthopaedics