Helmholtz Young Investigator Group Brain Mosaicism and Tumorigenesis

Neural stem and progenitor cells undergo tens of thousands cell division to generate 80 billion neurons in the human brain. Rapid cell division could result in DNA damage that may lead to genomic lesions to drive brain cancer initiation. Mouse model studies have shown that DNA repair factor inactivation in the p53-deficient mouse neural stem and progenitor cell resulted in medulloblastomas, one the most common and deadly brain cancers in childhood. In these mouse medulloblastomas, recurrent tumor suppressor gene Ptch1 deletion, oncogene Myc-N amplification, copy number variations and chromosomal translocations occur similar as in a subgroup of human medulloblastomas. These findings fueled the speculation that recurrent DNA breaks occurred during early brain development. Our prior study revealed over a hundred recurrent DNA break clusters, namely RDCs, colocalized at the body of transcribed genes in the neural stem and progenitor cells (Wei et al., 2016 and 2018). The majority of RDC containing genes encode proteins that control neuronal synaptic functions. In addition, human orthologs of most mouse RDC-genes were genetically disrupted in patients with neuropsychiatric disorders and brain cancers. Most RDC containing genes are very long and late replicating, two general features also observed in common fragile sites. These findings are generally perceived to be the remarkable beginning to understand neural stem cell genome instability and brain tumor initiation.

Our mission is to understand the biological function of recurrent DNA breaks in brain development and diseases. We will combine cell-line tools, mouse models, and state-of-the-art next generation sequencing methods to elucidate the key acting factors that lead to RDC, whether the 3-D chromatin architecture facilitate genomic structural variation, the temporal and spatial RDCs organization in the developing brain, and whether RDC breaks directly contribute to brain cancer and mental disorders.