scholarly journals Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response

2020 ◽  
Author(s):  
Kevin C. Johnson ◽  
Kevin J. Anderson ◽  
Elise T. Courtois ◽  
Floris P. Barthel ◽  
Frederick S. Varn ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stress Response ◽  
Environmental Stress ◽  
Single Cell ◽  
Intratumoral Heterogeneity ◽  
Cellular Plasticity ◽  
Environmental Stress Response ◽  
Integrative Framework ◽  
Epigenetic Instability ◽  
Somatic Copy Number Alterations

ABSTRACTGlioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. Our analyses support that somatic copy number alterations (SCNAs) promote epigenetic instability and that SCNAs largely precede epigenetic and transcriptomic diversification during glioma evolution. We confirmed the link between genetic and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response.

scholarly journals EPCO-27. GLIOMA SINGLE CELL MULTI-OMIC ANALYSES REVEALS REGULATORS OF PLASTICITY AND ADAPTIVE STRESS RESPONSE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii75-ii75
Author(s):  
Kevin Johnson ◽  
Kevin Anderson ◽  
Elise Courtois ◽  
Floris Barthel ◽  
Frederick Varn ◽  
...  
Keyword(s):  
Stress Response ◽  
Single Cell ◽  
Tumor Cells ◽  
Binding Sites ◽  
Copy Number ◽  
Epigenetic Mechanisms ◽  
Cellular Plasticity ◽  
Epigenetic Instability ◽  
Extracellular Stimuli ◽  
Cell Stress Response

Abstract Extensive intra- and intertumoral heterogeneity in glioma contributes to therapeutic resistance and poor patient outcomes. Alterations to DNA methylation (DNAme) modulate epigenetic homeostasis, allowing tumor cells to sample alternative cell states to promote tumorigenesis. However, the epigenetic mechanisms that promote cellular plasticity and regulate cell states are still poorly understood. To characterize the epigenetic mechanisms underlying glioma heterogeneity we profiled 914 single-cell methylomes, 55,284 single-cell transcriptomes, and bulk whole genomes across 11 patient samples spanning initial and recurrent time points and 3 molecular subtypes delineated by IDH mutation status. Local DNAme disorder, defined as epimutation burden, was increased in tumor cells relative to nontumor cells, higher in IDH wild-type than in IDH mutant glioma and was positively associated with copy number alteration (CNA). Epimutation was positively associated with transcriptional variability and enriched at genes involved in cellular differentiation. Epimutation was also increased in the binding sites of transcription factors (TFs) associated with response to extracellular stimuli, suggesting that stochastic DNAme alterations enable cellular plasticity and diverse responses to microenvironmental stressors. Integrative clustering of DNAme and scRNAseq profiles defined stem-like and differentiated-like cell states which exhibited differences in TF activity. Stem-like cells were enriched for differentially methylated binding sites of TFs associated with hypoxia response. scDNAme and scRNAseq-derived copy number profiles were compared with bulk copy number profiles and inferred tumor phylogenies to assess how the timing of CNAs impact epigenetic instability, with results suggesting that early CNA events propagate both genetic and epigenetic heterogeneity. Bulk longitudinal data was used to validate the relationship of epigenetic instability with CNA burden as well as differentially methylated binding sites of cell stress response TFs. Our work suggests that local DNAme disorder promotes cellular plasticity and enables adaptive response to cellular stress such as hypoxia.

Loss of alkaline ceramidase inhibits autophagy in Arabidopsis and plays an important role during environmental stress response

2018 ◽  
Vol 41 (4) ◽  
pp. 837-849 ◽  
Author(s):  
Ping Zheng ◽  
Jian-Xin Wu ◽  
Sunil Kumar Sahu ◽  
Hong-Yun Zeng ◽  
Li-Qun Huang ◽  
...  
Keyword(s):  
Stress Response ◽  
Environmental Stress ◽  
Environmental Stress Response

scholarly journals The environmental stress response causes ribosome loss in aneuploid yeast cells

2020 ◽  
Vol 117 (29) ◽  
pp. 17031-17040 ◽  
Author(s):  
Allegra Terhorst ◽  
Arzu Sandikci ◽  
Abigail Keller ◽  
Charles A. Whittaker ◽  
Maitreya J. Dunham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Stationary Phase ◽  
Environmental Stress ◽  
Budding Yeast ◽  
Expression Patterns ◽  
Yeast Cells ◽  
Specific Gene ◽  
Environmental Stress Response ◽  
Cellular Stresses

Aneuploidy, a condition characterized by whole chromosome gains and losses, is often associated with significant cellular stress and decreased fitness. However, how cells respond to the aneuploid state has remained controversial. In aneuploid budding yeast, two opposing gene-expression patterns have been reported: the “environmental stress response” (ESR) and the “common aneuploidy gene-expression” (CAGE) signature, in which many ESR genes are oppositely regulated. Here, we investigate this controversy. We show that the CAGE signature is not an aneuploidy-specific gene-expression signature but the result of normalizing the gene-expression profile of actively proliferating aneuploid cells to that of euploid cells grown into stationary phase. Because growth into stationary phase is among the strongest inducers of the ESR, the ESR in aneuploid cells was masked when stationary phase euploid cells were used for normalization in transcriptomic studies. When exponentially growing euploid cells are used in gene-expression comparisons with aneuploid cells, the CAGE signature is no longer evident in aneuploid cells. Instead, aneuploid cells exhibit the ESR. We further show that the ESR causes selective ribosome loss in aneuploid cells, providing an explanation for the decreased cellular density of aneuploid cells. We conclude that aneuploid budding yeast cells mount the ESR, rather than the CAGE signature, in response to aneuploidy-induced cellular stresses, resulting in selective ribosome loss. We propose that the ESR serves two purposes in aneuploid cells: protecting cells from aneuploidy-induced cellular stresses and preventing excessive cellular enlargement during slowed cell cycles by down-regulating translation capacity.

The root of ABA action in environmental stress response

2013 ◽  
Vol 32 (7) ◽  
pp. 971-983 ◽  
Author(s):  
Jing Han Hong ◽  
Seng Wee Seah ◽  
Jian Xu
Keyword(s):  
Stress Response ◽  
Environmental Stress ◽  
Environmental Stress Response
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