%0 Generic
%A Bellvis Zambrano, Pablo
%D 2017
%F heidok:23225
%R 10.11588/heidok.00023225
%T Role of histone variant H3.3 in neurogenesis and gliomagenesis
%U https://archiv.ub.uni-heidelberg.de/volltextserver/23225/
%X Glioblastoma multiforme (GBM) (WHO classification IV) is the most common primary malignant brain tumor with a poor prognosis in both adults and children. In the last years several studies have shown that 44% of glioblastoma multiforme tumors are characterized by the same histone mutations manifested in the histone variant H3.3. These studies strongly implicate the K27M amino acid substitution in H3.3 in the pathogenesis of diffuse intrinsic pontine glioma (DIPG). Also, H3.3 has been recently linked to multiple processes in the brain like neuronal specialization, synapses, cognition and contextual fear memory.  In this study, two important tools were generated to investigate the role of H3.3 in the brain. Firstly, making use of the RCAS/TVA system, we established a DIPG mouse model overexpressing constitutively active AKT, PDGFB, Luciferase and floxed H3.3K27M in Nestin expressing cells in the brain. This model resembles High Grade Gliomas (HGGs) in histology and shows a key feature observed in the human DIPG tumors that is the H3K27me3 loss. In combination with Bioluminescence Imaging (BLI), the model enables monitoring of tumor growth. The model allowed for H3K27me3 recovery after deletion of H3.3K27M.  Secondly, we successfully established an inducible RFP-tagged H3f3b-overexpressing mouse line. By modifying a Bacterial Artificial Chromosome (BAC) carrying the H3f3b gene, the fusion protein H3f3b-RFP-ERT2 was overexpressed. This construct allows for histone tracing in living behaving animals.