Chromatin landscapes reveal developmentally encoded transcriptional states that define human glioblastoma
| Autor: | Xiuxing Wang, Wenchao Zhou, Lukas Chavez, Shideng Bao, Andrew E Sloan, Michael A. Vogelbaum, Jean A. Bernatchez, Kelsey C. Bertrand, Peter C. Scacheri, Q Wu, Irtisha Singh, Clarence K. Mah, Stephen C. Mack, Jair L. Siqueira-Neto, Zhixin Qiu, Andrew R. Morton, Rosie Villagomez, Sisi Lai, Gene H. Barnett, Christine Lee, Rachel A. Hirsch, Briana C. Prager, Jeremy N. Rich, Zhe Zhu, Ryan C. Gimple, Charles Y. Lin, Leo J.Y. Kim |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
endocrine system Transcription Genetic Carcinogenesis Technical Advances Immunology Mice SCID Biology Cohort Studies 03 medical and health sciences Mice 0302 clinical medicine Neural Stem Cells Transcription (biology) Mice Inbred NOD Cell Line Tumor Immunology and Allergy Animals Humans Enhancer Gene Transcription factor Research Articles Regulation of gene expression Brain Neoplasms Neural stem cell Chromatin 3. Good health Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology 030220 oncology & carcinogenesis Neoplastic Stem Cells Heterografts Stem cell Glioblastoma Transcriptome Transcription Factors |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | Mack et al. defined active chromatin landscapes of glioblastoma stem cells (GSCs) and primary tumor specimens, revealing novel transcriptional regulatory circuits and therapeutic targets. Super-enhancers identified essential transcription factors that underlie GSC identity and intertumoral diversity, potentially informing precision medicine. Glioblastoma is an incurable brain cancer characterized by high genetic and pathological heterogeneity. Here, we mapped active chromatin landscapes with gene expression, whole exomes, copy number profiles, and DNA methylomes across 44 patient-derived glioblastoma stem cells (GSCs), 50 primary tumors, and 10 neural stem cells (NSCs) to identify essential super-enhancer (SE)–associated genes and the core transcription factors that establish SEs and maintain GSC identity. GSCs segregate into two groups dominated by distinct enhancer profiles and unique developmental core transcription factor regulatory programs. Group-specific transcription factors enforce GSC identity; they exhibit higher activity in glioblastomas versus NSCs, are associated with poor clinical outcomes, and are required for glioblastoma growth in vivo. Although transcription factors are commonly considered undruggable, group-specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition. These data demonstrate that transcriptional identity can be leveraged to identify novel dependencies and therapeutic approaches. Graphical Abstract |
| Databáze: | OpenAIRE |
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