TY  - JOUR
AU  - Wang, Wanchen
AU  - Kumegawa, Kohei
AU  - Chapman, Owen S
AU  - Shiraishi, Ryo
AU  - Xiao, Zhize
AU  - Okonechnikov, Konstantin
AU  - Sun, Yang
AU  - Pfister, Stefan M
AU  - Feng, Weijun
AU  - Uesaka, Naofumi
AU  - Hoshino, Mikio
AU  - Takahashi, Satoru
AU  - Korshunov, Andrey
AU  - Chavez, Lukas
AU  - Maruyama, Reo
AU  - Kawauchi, Daisuke
TI  - Chromatin modification abnormalities by CHD7 and KMT2C loss promote medulloblastoma progression.
JO  - Cell reports
VL  - 44
IS  - 5
SN  - 2211-1247
CY  - Maryland Heights, MO
PB  - Cell Press
M1  - DKFZ-2025-01043
SP  - 115673
PY  - 2025
N1  - Volume 44, Issue 5, 27 May 2025, 115673
AB  - Medulloblastoma (MB), a common malignant pediatric brain tumor arising in the cerebellum, is characterized by mutations in chromatin modifiers, highlighting the significance of chromatin modification abnormalities in its progression. While animal models have effectively demonstrated this, a comprehensive evaluation of the oncogenic potential of these mutations remains incomplete. In this study, we use CRISPR-mediated gene editing to knock out chromatin modifier genes mutated in human SHH MB, along with the Ptch1 gene, in cerebellar granule neuron progenitors of neonatal mice. This reveals that depletion of Chd7 and Kmt2c accelerates tumor growth. Multi-layered omics analysis uncovers that inhibition of the neuronal differentiation program by chromatin dysregulation is a key signaling pathway in tumor progression. Additionally, forced expression of Neurod1, a common target of these chromatin modifiers, inhibits proliferation and promotes differentiation. These findings highlight converging chromatin modification abnormalities from distinct mutations in Sonic Hedgehog MB and suggest that epigenetic drugs activating neuronal genes have significant potential as novel treatments.
KW  - CHD7 (Other)
KW  - CP: Cancer (Other)
KW  - KMT2C (Other)
KW  - brain tumor (Other)
KW  - chromatin modifications (Other)
KW  - medulloblastoma (Other)
KW  - mouse model (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40393452
DO  - DOI:10.1016/j.celrep.2025.115673
UR  - https://inrepo02.dkfz.de/record/301504
ER  -