Monday, May 19, 2025
5/19/2025
The function of chromatin remodeling in the patterning of the salamander limb - PROJECT SUMMARY: Nearly two million people in the United States are living with limb loss and the devastating effects that this loss has on their quality of life and economic status. The long-term goal of this research is to make it possible for these patients to regrow their extremities by inducing an endogenous regenerative response. Accomplishing this goal will require the study of endogenous limb regeneration in animals that do this naturally, such as the Mexican Axolotl. One essential question that has not been resolved is how the mature limb cells become capable of making the pattern of the regenerated limb. Studies have shown that prior to the formation of new pattern, the cells that contribute to the regenerate acquire positional plasticity that allows them to become reprogrammed by patterning signals in the regenerating environment. Preliminary studies have identified that 1) a combination of FGF and BMP signaling are sufficient to make the mature limb cells positionally plastic, and 2) that a significant loss the inhibitory chromatin mark H3K27me3 occurs in limb cells when they acquire positional plasticity. Members of both the FGF and BMP signaling cascades have been previously shown in other systems to interact with chromatin modifying enzymes which can lead to the loss of H3K27me3 on specific genes. The central hypothesis of this study is that BMP and FGF signaling are required for the chromatin modifications that make limb cells capable of acquiring new pattern. To investigate how FGF and BMP signaling induce positional plasticity a two-pronged approach will be employed. The experiments in Aim 1 will utilize H3K27me ChIP-seq and RNA-seq to identify gene candidates that are directly downstream of BMP and FGF signaling and determine whether these gene targets are mutually dependent on both BMP and FGF signaling. Aim 2 will employ FACS, quantitative microscopy, and phenomenological assays to evaluate whether the mitogenic activity of FGF and BMP is required for both the loss of H3K27me3 and the acquisition of positional plasticity.
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