Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Mutant cells show decreased levels and altered distribution of H3K27 trimethylation (H3K27me3). How these chromatin changes are established genome-wide and lead to tumorigenesis remains unclear. Here we show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells in Caenorhabditis elegans. By genetically inducing changes in the H3.3 distribution, we demonstrate that both H3.3K27M and pre-existing H3K27me3 act locally and antagonistically on Polycomb Repressive Complex 2 (PRC2) in a concentration-dependent manner. The heterochromatin changes result in extensive gene misregulation, and genetic screening identified upregulation of JNK as an underlying cause of the germcell aberrations. Moreover, JNK inhibition suppresses the replicative fate in human tumor-derived H3.3K27M cells, thus establishing C. elegans as a powerful model for the identification of potential drug targets for treatment of H3.3K27M tumors.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555832 | PMC |
| http://dx.doi.org/10.1038/s41467-019-10404-9 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Poly ADP-ribosylation regulates Arc expression and promotes adaptive stress-coping.
Psychopharmacology (Berl)
January 2025
Department of Molecular Biology, Ariel University, Ariel, Israel.
Rationale: Rapid adaptation to stressful events is essential for survival and requires acute stress response and stress-coping strategy. However, the molecular mechanisms that govern this coping strategy have yet to be fully discovered.
Objectives: This study aims to investigate the effects of poly ADP-ribosylation (PARylation) on stress-coping strategies following acute stress and to identify the target genes influenced by Parp1-induced histone PARylation.
Maternal asthma imprints fetal lung ILC2s via glucocorticoid signaling leading to worsened allergic airway inflammation in murine adult offspring.
Nat Commun
January 2025
Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
The root of asthma can be linked to early life, with prenatal environments influencing risk. We investigate the effects of maternal asthma on the offspring's lungs during fetal and adult life. Adult offspring of asthmatic mothers show an increase in lung group 2 innate lymphoid cell (ILC2) number and function with allergen-induced lung inflammation.
View Article and Find Full Text PDFEmergence of fungal hybrids - potential threat to humans.
Microb Pathog
January 2025
Cell Biology and Molecular Genetics, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, INDIA. Electronic address:
Fungal hybrids arise through the interbreeding of distinct species. This hybridization process fosters increased genetic diversity and the emergence of new traits. Mechanisms driving hybridization include the loss of heterozygosity, copy number variations, and horizontal gene transfer.
View Article and Find Full Text PDFDiversification and recurrent adaptation of the synaptonemal complex in Drosophila.
PLoS Genet
January 2025
Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada.
The synaptonemal complex (SC) is a protein-rich structure essential for meiotic recombination and faithful chromosome segregation. Acting like a zipper to paired homologous chromosomes during early prophase I, the complex is a symmetrical structure where central elements are connected on two sides by the transverse filaments to the chromatin-anchoring lateral elements. Despite being found in most major eukaryotic taxa implying a deeply conserved evolutionary origin, several components of the complex exhibit unusually high rates of sequence turnover.
View Article and Find Full Text PDFChromatin remodeling enzymes play a crucial role in the organization of chromatin, enabling both stability and plasticity of genome regulation. These enzymes use a Snf2-type ATPase motor to move nucleosomes, but how they translocate DNA around the histone octamer is unclear. Here we use cryo-EM to visualize the continuous motion of nucleosomal DNA induced by human chromatin remodeler SNF2H, an ISWI family member.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!