The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential

BMC Biology

卷:20

S. Matkovich¹  R. Prakasam²  P. Gontarz²  K. L. Kroll²  A. H. Kim³  H. Yano³  N. Kfoury-Beaumont⁴  J. B. Rubin⁵  J. S. Lagas⁵  S. Pondugula⁵  L. Yang⁵ 

[1] Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine;

[2] Department of Developmental Biology, Washington University School of Medicine;

[3] Department of Neurological Surgery, Washington University School of Medicine;

[4] Department of Neurosurgery, University of California in San Diego;

[5] Department of Pediatrics, Washington University School of Medicine;

关键词: DIPG;    H3K27M;    Epigenetics;    Aberrant differentiation;    Pediatric brain tumors;   

DOI  :  10.1186/s12915-022-01324-0

来源: DOAJ

【 摘 要 】

Abstract Background Neurodevelopmental disorders increase brain tumor risk, suggesting that normal brain development may have protective properties. Mutations in epigenetic regulators are common in pediatric brain tumors, highlighting a potentially central role for disrupted epigenetic regulation of normal brain development in tumorigenesis. For example, lysine 27 to methionine mutation (H3K27M) in the H3F3A gene occurs frequently in Diffuse Intrinsic Pontine Gliomas (DIPGs), the most aggressive pediatric glioma. As H3K27M mutation is necessary but insufficient to cause DIPGs, it is accompanied by additional mutations in tumors. However, how H3K27M alone increases vulnerability to DIPG tumorigenesis remains unclear. Results Here, we used human embryonic stem cell models with this mutation, in the absence of other DIPG contributory mutations, to investigate how H3K27M alters cellular proliferation and differentiation. We found that H3K27M increased stem cell proliferation and stem cell properties. It interfered with differentiation, promoting anomalous mesodermal and ectodermal gene expression during both multi-lineage and germ layer-specific cell specification, and blocking normal differentiation into neuroectoderm. H3K27M mutant clones exhibited transcriptomic diversity relative to the more homogeneous wildtype population, suggesting reduced fidelity of gene regulation, with aberrant expression of genes involved in stem cell regulation, differentiation, and tumorigenesis. These phenomena were associated with global loss of H3K27me3 and concordant loss of DNA methylation at specific genes in H3K27M-expressing cells. Conclusions Together, these data suggest that H3K27M mutation disrupts normal differentiation, maintaining a partially differentiated state with elevated clonogenicity during early development. This disrupted response to early developmental cues could promote tissue properties that enable acquisition of additional mutations that cooperate with H3K27M mutation in genesis of DMG/DIPG. Therefore, this work demonstrates for the first time that H3K27M mutation confers vulnerability to gliomagenesis through persistent clonogenicity and aberrant differentiation and defines associated alterations of histone and DNA methylation.

【 授权许可】

Unknown