Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states

Chaligné, Ronan; Gaiti, Federico; Silverbush, Dana; Schiffman, Joshua S.; Weisman, Hannah; Kluegel, Lloyd; Gritsch, Simon; Deochand, Sunil; Castro, L Nicolas Gonzalez; Richman, Alyssa; Klughammer, Johanna; Biancalani, Tommaso; Muus, Christoph; Sheridan, Caroline; Alonso, Alicia; Izzo, Franco; Park, Jane; Rozenblatt-Rosen, Orit; Regev, Aviv; Suvà, Mario L.; Landau, Dan A.

doi:10.1038/s41588-021-00927-7

Cited by 152 publications

(135 citation statements)

References 113 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…This result does not surprise on one hand because active cellular programs in neoplastic brain tissue differ substantially from that in the healthy brain. On the other hand, the observed correspondence of DNA-methylation patterns confirms the fact that cell-of-origin DNA methylation signatures are largely maintained during carcinogenesis [86,89,90]. In summary, comparison of aging brain with LGG supports the view that GBM-like IDH-wt LGG exhibit higher cellular plasticity activated in the developing healthy brain while IDH-mut LGG have a more stable differentiation hierarchy more resembling the aged brain (Figure 8f).…”

Section: Relations Between the Aging Brain And Glioma Heterogeneitysupporting

confidence: 74%

“…The observed similarity can be mainly attributed to the age profile of specific GCIMP genes differentially methylated between IDH-mut and IDH-wt gliomas [81] which resembles the aging profile of PRC2-targets weakly methylated in early developmental stages of the brain (Figure 8e). Recent studies show that PRC2-targets associate with open chromatin states as well as with hypomethylation which is a key determinant of glioma stem cells ( [86] and references cited therein). This epigenetic encoding of glioma supports the parallels between glioma differentiation and physiological neurodevelopment where stemness is also marked by PRC2 target hypomethylation.…”

Section: Relations Between the Aging Brain And Glioma Heterogeneitymentioning

confidence: 99%

See 1 more Smart Citation

The Transcriptome and Methylome of the Developing and Aging Brain and Their Relations to Gliomas and Psychological Disorders

Loeffler‐Wirth

Hopp

Schmidt

et al. 2022

Cells

View full text Add to dashboard Cite

Mutually linked expression and methylation dynamics in the brain govern genome regulation over the whole lifetime with an impact on cognition, psychological disorders, and cancer. We performed a joint study of gene expression and DNA methylation of brain tissue originating from the human prefrontal cortex of individuals across the lifespan to describe changes in cellular programs and their regulation by epigenetic mechanisms. The analysis considers previous knowledge in terms of functional gene signatures and chromatin states derived from independent studies, aging profiles of a battery of chromatin modifying enzymes, and data of gliomas and neuropsychological disorders for a holistic view on the development and aging of the brain. Expression and methylation changes from babies to elderly adults decompose into different modes associated with the serial activation of (brain) developmental, learning, metabolic and inflammatory functions, where methylation in gene promoters mostly represses transcription. Expression of genes encoding methylome modifying enzymes is very diverse reflecting complex regulations during lifetime which also associates with the marked remodeling of chromatin between permissive and restrictive states. Data of brain cancer and psychotic disorders reveal footprints of pathophysiologies related to brain development and aging. Comparison of aging brains with gliomas supports the view that glioblastoma-like and astrocytoma-like tumors exhibit higher cellular plasticity activated in the developing healthy brain while oligodendrogliomas have a more stable differentiation hierarchy more resembling the aged brain. The balance and specific shifts between volatile and stable and between more irreversible and more plastic epigenomic networks govern the development and aging of healthy and diseased brain.

show abstract

Section: Relations Between the Aging Brain And Glioma Heterogeneitysupporting

confidence: 74%

Section: Relations Between the Aging Brain And Glioma Heterogeneitymentioning

confidence: 99%

The Transcriptome and Methylome of the Developing and Aging Brain and Their Relations to Gliomas and Psychological Disorders

Loeffler‐Wirth

Hopp

Schmidt

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…More importantly, hypermethylated regions in ic-GSCs showed a clear increment in polycomb repressed and bivalent poised marks, a phenomenon that was extended to the HLA-B and HLA-C promoter regions in stem-related samples. A similar phenomenon has recently been observed by Chaligne et al 39, where polycomb activity may establish bivalent domains at hypomethylated promoters in GBM stem-like cells. Accordingly, Burr et al 40 reported preprint (which was not certified by peer review) is the author/funder.…”

Section: Epigenetic Changes Behind the Ic-gsc Transcriptome Reprogrammingsupporting

confidence: 84%

Glioblastoma embryonic-like stem cells exhibit immune-evasive phenotype

Sesé

Iñiguez

Ensenat³

et al. 2021

Preprint

View full text Add to dashboard Cite

Glioma stem cells (GSCs) are a subset of cells with self-renewal and tumor-initiating capacities that are thought to participate in drug resistance and immune evasion mechanisms in glioblastoma (GBM). Given GBM heterogeneity, we hypothesized that GSCs might also display cellular hierarchies associated with different degrees of stemness. We evaluated a single-cell RNA-seq glioblastoma dataset (n = 28) and identified a stem cell population co-expressing high levels of embryonic pluripotency markers, named core glioma stem cells (c-GSCs). This embryonic-like population represents 4.22% of the tumor cell mass, and pathway analysis revealed an upregulation of stemness and downregulation of immune-associated pathways. Using induced pluripotent stem cell technology, we generated an in vitro model of c-GSCs by reprogramming glioblastoma patient-derived cells into induced c-GSCs (ic-GSCs). Immunostaining of ic-GSCs showed high expression of embryonic pluripotency markers and downregulation of antigen presentation HLA proteins, mimicking its tumoral counterpart. Transcriptomic analysis revealed a strong agreement of enriched biological pathways between tumor c-GSCs and in vitro ic-GSCs (k = 0.71). Integration of ic-GSC DNA methylation and gene expression with chromatin state analysis of epigenomic maps (n = 833) indicated that polycomb repressive marks downregulate HLA genes in stem-like phenotype. Together, we identified c-GSCs as a GBM cell population with embryonic signatures and poor immunogenicity. Genome-scale transcriptomic and epigenomic profiling provide a valuable resource for studying immune evasion mechanisms governing c-GSCs and identifying potential therapeutic targets for GBM immunotherapy.

show abstract

“…DNA-based single-cell assays can detect CNV in targeted regions of interest (scDNA-seq) or globally across the entire nuclear genome [e.g. single-cell whole genome (scWGS-seq) (68)(69)(70), assay for transposase-accessible chromatin using sequencing (scATAC-seq) (71,72) or single-cell sequencing of DNA methylation (scDNAme) (73)]. Targeted approaches enable detection of CNV changes at higher coverage and better cost efficiency, but require design of primers for these target regions, which can be accomplished either through large panels for recurrent genetic events or personalized solutions based on previous analyses (9,74).…”

Section: Copy Number Changesmentioning

confidence: 99%

Natural Barcodes for Longitudinal Single Cell Tracking of Leukemic and Immune Cell Dynamics

Penter

Gohil

2022

Front. Immunol.

View full text Add to dashboard Cite

Blood malignancies provide unique opportunities for longitudinal tracking of disease evolution following therapeutic bottlenecks and for the monitoring of changes in anti-tumor immunity. The expanding development of multi-modal single-cell sequencing technologies affords newer platforms to elucidate the mechanisms underlying these processes at unprecedented resolution. Furthermore, the identification of molecular events that can serve as in-vivo barcodes now facilitate the tracking of the trajectories of malignant and of immune cell populations over time within primary human samples, as these permit unambiguous identification of the clonal lineage of cell populations within heterogeneous phenotypes. Here, we provide an overview of the potential for chromosomal copy number changes, somatic nuclear and mitochondrial DNA mutations, single nucleotide polymorphisms, and T and B cell receptor sequences to serve as personal natural barcodes and review technical implementations in single-cell analysis workflows. Applications of these methodologies include the study of acquired therapeutic resistance and the dissection of donor- and host cellular interactions in the context of allogeneic hematopoietic stem cell transplantation.

show abstract

Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states

Cited by 152 publications

References 113 publications

The Transcriptome and Methylome of the Developing and Aging Brain and Their Relations to Gliomas and Psychological Disorders

The Transcriptome and Methylome of the Developing and Aging Brain and Their Relations to Gliomas and Psychological Disorders

Glioblastoma embryonic-like stem cells exhibit immune-evasive phenotype

Natural Barcodes for Longitudinal Single Cell Tracking of Leukemic and Immune Cell Dynamics

Contact Info

Product

Resources

About