Cell fate plasticity and transdifferentiation during development and regeneration of endodermal organs

• Applicants: Professor Dr. Jan Philipp Junker; Professor Dr. Nikolay Ninov, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology ; Developmental Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458913362

Cell fate decisions happen with ease during development due to the high plasticity of embryonic cells. However, plasticity becomes restricted as the organism develops into an adult. As a result, the process of adult tissue regeneration, which relies on cell plasticity, is limited and declines further during aging. An important challenge in the field of regenerative biology is to identify and remove the "roadblocks" that impede cell fate changes in order to promote regenerative repair of damaged organs. Here, we propose to identify and remove roadblocks to regeneration using single-cell genomics and targeted chromatin remodeling approaches. To this end, we will compare cell fate changes during development and regeneration by studying natural and injury-induced cell plasticity at the single-cell level. Our project has three main goals. The first goal is to "catch" cells in the act of moving from cell fate A to cell fate B using technologies that combine RNA labeling with single-cell transcriptomics (single-cell SLAM-seq). The second goal is to analyze the underlying chromatin changes and active enhancer landscape using single-cell ATAC-seq to define permissive and restrictive signatures. The final goal is to enhance regeneration by manipulating cell fate using targeted chromatin remodeling in defined cell types.For our work, we will focus on the pancreatic islet due to the biomedical implications of its function for diabetes research and due to the large number of described cell fate transitions and transdifferentiation events in its development and regeneration. We will use scSLAM-seq to identify the molecular switches that orchestrate cell fate transitions during development and regeneration, and we will use scATAC-seq to identify chromatin changes that control transdifferentiation. We will then apply targeted chromatin remodeling in defined cell types in order to enhance the regeneration of ß-cells.To bring our ambitious research goals to fruition, the project will combine the expertise of the Ninov lab (TU Dresden) in cell differentiation in the pancreas with the expertise of the Junker lab (MDC Berlin) on single-cell genomics analysis of cell fate decisions. Thus, we will join efforts, complementary expertise, and demonstrated collaborative capacity to address the following outstanding questions:1. To define the roadblocks of cell plasticity as an embryo transitions into an adult. 2. To identify the effectors of cell plasticity during regeneration.3. To remove the roadblocks to regeneration in order to enhance cell plasticity.

• DFG Programme: Research Grants