Helmholtz Young Investigator Group Brain Mosaicism and Tumorigenesis
Dr. Pei-Chi Wei
Mouse E15.5 embryo stains for Tbr2 (green), Satb2 (red), Ctip2 (purple) and DAPI (blue). Image credit: Giulia Di Muzio, Leica Mica system
© dkfz.de
Neural progenitor cells undergo tens of thousands of cell divisions to generate the 170 billion neurons and astrocytes in a human brain. Most human and murine brain cells are produced within 24 weeks to 11 days in utero. This process is tightly regulated spatially and temporally, resulting in an average of 350-400g of the newborn human brain. How do neural stem/progenitor cells know when to stop proliferation? How (and why) do they prolong the duration of each cell cycle? Whether a fast-proliferating program render more severe DNA damage to the brain progenitor cells? These fundamental questions are highly relevant to brain cancer's initiation, progression, and evolution.
Dr. Wei’s lab studies brain genome instability and somatic mosaicism. We are mainly an experimental and genomics laboratory, collaborative, with long-standing expertise in developing in vitro and in vivo tools to reveal genomic scars that resulted from altered DNA replication. We are highly interested in developing AI tools to extract hidden information from multidimensional genomics data at an unpresidential resolution, to understand the source of recurrent DNA breaks in neural stem/progenitor cells. Our three main research directions offer sufficient flexibility for incoming students and scientists to learn, develop, and, ultimately, create a specific and unique niche.
First, we investigate the source of recurrent DNA breaks in the neural stem and progenitor cells. We found that genes encode proteins that regulate neuronal crosstalk frequently break in brain progenitor cells. These genes are hotspots for genome aberrant in neuropsychiatric and cancer. Our laboratory has established in vitro cell culture system, empowering versatile genome editing to control gene expression status in neural progenitor cells. We have strong expertise in mapping DNA breaks at a nucleotide resolution. Current advances in defining DNA breaks on replication forks are being finalized in a manuscript in preparation. In addition, we are actively looking into the molecular “scissors” that are responsible for the recurrent DNA breaks. [Helmholtz Young Investigator Grant + ERC starting grant]
Second, we are working on an in vivo model to allow DNA break mapping in a temporal and spatial manner. DNA breaks are drivers for small and large genome alterations. The timing and position of when the DNA break occurs determine genome structure and, in some cases, may reveal the ancestry of the cells. In collaboration with the transgenic laboratory at the DKFZ, we are preparing a mouse model that allows capturing spontaneous DNA breaks during embryonic neurogenesis. We aim to compare the landscape of in vivo captured DNA breaks in mouse embryos that are normally developed or have encountered short-term replication stress. [ERC starting grant]
Third, we are developing a mouse model where the intrinsic replication stress is amplified in neural progenitor cells. The existing in vivo animal model to study replication stress involves in deletion of tumor suppressor genes or overexpressing oncogenes. We propose to avoid the predisposed “driver” effect, which would affect cell fate and clonal trajectory. In this model, the neural progenitor cells undergo more and faster cell cycles. We are investigating the outcome, in particular the genome structure variation in the neural progenitor cell genome, and the overall implication on brain disease breakpoints. [Helmholtz Young Investigator Grant + ERC starting grant].
