DNA methylation is an epigenetic modification required for transposable element (TE) silencing, genome stability, and genomic imprinting. Although DNA methylation has been intensively studied, the dynamic nature of methylation among different species has just begun to be understood. Here we summarize the recent progress in research on the wide variation of DNA methylation in different plants, organs, tissues, and cells; dynamic changes of methylation are also reported during plant growth and development as well as changes in response to environmental stresses. Overall DNA methylation is quite diverse among species, and it occurs in CG, CHG, and CHH (H = A, C, or T) contexts of genes and TEs in angiosperms. Moderately expressed genes are most likely methylated in gene bodies. Methylation levels decrease significantly just upstream of the transcription start site and around transcription termination sites; its levels in the promoter are inversely correlated with the expression of some genes in plants. Methylation can be altered by different environmental stimuli such as pathogens and abiotic stresses. It is likely that methylation existed in the common eukaryotic ancestor before fungi, plants and animals diverged during evolution. In summary, DNA methylation patterns in angiosperms are complex, dynamic, and an integral part of genome diversity after millions of years of evolution.

Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.

Glioma stem-like and tumor cells exhibit phenotypic plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. In this study, we employed single-cell and whole transcriptomic analyses to uncover that radiation-stress induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular gene regions allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity using a small molecule inhibitor C646 or gene knockdown reverses the epigenetic changes induced by radiation, inhibits the adaptive conversion of GSC into vascular-like cells, reduces tumor growth and enhances animal survival. Our findings highlight an important role for P300 in mediating adaptive response of glioma stem cells to therapeutic-stress, and opens a new therapeutic avenue for preventing glioma recurrence. Citation Format: Sree Deepthi Muthukrishnan, Riki Kawaguchi, Pooja Nair, Alvaro Alvarado, Harley Kornblum. P300 histone acetyltransferase mediates glioma stem cell adaptive response to therapeutic stress [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B011.

Radiation-resistant glioma cells exhibit phenotypic plasticity leading to aggressive tumor recurrence. However, the underlying molecular mechanisms remain to be elucidated. Here, we employed single-cell and whole transcriptomic analyses to discover that radiation induces a dynamic shift in proportions and functional states of glioma cells allowing for acquisition of vascular- and mesenchymal-like phenotypes. The primary phenotypic switch induced by radiation is transdifferentiation to endothelial-like and pericyte-like cells. In turn, the transdifferentiated cells promote proliferation of radiated tumor cells, and their selective depletion results in reduced tumor growth post-treatment. The acquisition of vascular-like phenotype is driven by increased chromatin accessibility in vascular genes, and blocking P300-mediated histone acetyltransferase activity prior to radiation inhibits vascular transdifferentiation and tumor growth. Our findings indicate that radiation reprograms glioma cells driving vascular transdifferentiation and tumor recurrence, and highlights P300 HAT inhibitor as a potential therapeutic target for preventing GBM relapse.

Therapy-resistant glioma cells elicit remarkable phenotypic plasticity leading to aggressive tumor recurrence. Here, we used single-cell and whole transcriptomic sequencing to uncover that radiation treatment induces a dynamic shift in functional states of glioma cells allowing for acquisition of either stem-like, mesenchymal-like or vascular-like phenotypes. The predominant phenotype switch induced by radiation in surviving tumor cells is the vascular-like cell state, resulting in transdifferentiation to endothelial-like and pericyte-like cells in distinct cell clusters. The transdifferentiated endothelial-like and pericyte-like cells secrete trophic factors to support proliferation of tumor cells, and their selective ablation results in reduced tumor growth and recurrence post-treatment. Mechanistically, the acquisition of vascular-like phenotype is driven by increased acetylation and chromatin accessibility in vascular genes and in regions for binding of vascular specification transcription factors. Blocking histone acetylation using a small molecule inhibitor targeting P300 histone acetyltransferase activity prior to radiation treatment inhibits the vascular-like transdifferentiation of glioma cells and tumor growth. Our findings indicate that radiation therapy-induces rewiring of glioma cells that promotes vascular cell-like transdifferentiation, tumor growth and recurrence.