Trimethylation of H3K27 during human cerebellar development in relation to medulloblastoma
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Shahryar E. Mir1,2, Michiel Smits2, Dennis Biesmans1,2, Machteld Julsing2, Marianna Bugiani3, Eleonora Aronica4, Gertjan J.L. Kaspers1,2, Jacqueline Cloos1,2,5, Thomas Würdinger2,6 and Esther Hulleman1,2
1Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
2Neuro-oncology Research Group, Departments of Neurosurgery and Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
3Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
4Department of (Neuro) Pathology, Academic Medical Center and Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, The Netherlands
5Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands
6Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Esther Hulleman, email: [email protected]
Keywords: medulloblastoma, cerebellum, brain development, histone 3 trimethylation, immunohistochemistry
Received: June 21, 2015 Accepted: August 17, 2017 Published: September 08, 2017
Medulloblastoma (MB), the most common malignant childhood brain tumor, encompasses a collection of four clinically and molecularly distinct tumor subgroups, i.e. WNT, SHH, Group 3 and Group 4. These tumors are believed to originate from precursor cells during cerebellar development. Although the exact etiology of these brain tumors is not yet known, histone modifications are increasingly recognized as key events during cerebellum development and MB tumorigenesis. Recent studies show that key components involved in post-translational modifications of histone H3 lysine 27 (H3K27) are commonly deregulated in MB. In this descriptive study, we have investigated the trimethylation status of H3K27, as well as the expression of the H3K27 methylase EZH2 and demethylases KDM6A and KDM6B, during human cerebellum development in relation to MB. H3K27 Trimethylation status differed between the MB subgroups. Moreover, trimethylation of H3K27 and expression of its modifiers EZH2, KDM6A and KDM6B were detected in a spatio-temporal manner during development of the human cerebellum, with consistent high occurrence in the four proliferative zones, which are believed to harbor the precursor cells of the different MB subgroups. Our results suggest that H3K27 trimethylation in MB is deregulated by EZH2, KDM6A and KDM6B. Moreover, we provide evidence that during development of the human cerebellum H3K27me3 and its regulators are expressed in a spatio-temporal manner.
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