Abstract
The intrinsic drivers of migration in glioblastoma (GBM) are poorly understood. To better capture the native molecular imprint of GBM and its developmental context, here we isolate human stem cell populations from GBM (GSC) and germinal matrix tissues and map their chromatin accessibility via ATAC-seq. We uncover two distinct regulatory GSC signatures, a developmentally shared/proliferative and a tumor-specific/migratory one in which TEAD1/4 motifs are uniquely overrepresented. Using ChIP-PCR, we validate TEAD1 trans occupancy at accessibility sites within AQP4, EGFR, and CDH4. To further characterize TEAD's functional role in GBM, we knockout TEAD1 or TEAD4 in patient-derived GBM lines using CRISPR-Cas9. TEAD1 ablation robustly diminishes migration, both in vitro and in vivo, and alters migratory and EMT transcriptome signatures with consistent downregulation of its target AQP4. TEAD1 overexpression restores AQP4 expression, and both TEAD1 and AQP4 overexpression rescue migratory deficits in TEAD1-knockout cells, implicating a direct regulatory role for TEAD1-AQP4 in GBM migration.
MeSH 主题词
Aquaporin 4/genetics
Cell Movement/genetics
Chromatin/genetics,metabolism
Chromatin Immunoprecipitation
DNA-Binding Proteins/deficiency,genetics,metabolism
ErbB Receptors/genetics
Gene Expression
Gene Expression Regulation, Neoplastic
Glioblastoma/genetics,physiopathology
Humans
Neoplasm Invasiveness/genetics
Neoplastic Stem Cells/cytology
Nuclear Proteins/deficiency,genetics,metabolism
Nucleotide Motifs
TEA Domain Transcription Factors
Transcription Factors/deficiency,genetics,metabolism
Transcriptome/genetics
Transplantation, Heterologous
化学物质
AQP4 protein, human
Aquaporin 4
Chromatin
DNA-Binding Proteins
Nuclear Proteins
TEA Domain Transcription Factors
TEAD1 protein, human
Transcription Factors
EGFR protein, human
ErbB Receptors
作者与单位
共 11 位作者，点击展开单位 / ORCID
Tome-Garcia Jessica
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. | Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Erfani Parsa
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. | Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Nudelman German
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Tsankov Alexander M
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Katsyv Igor
Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Tejero Rut
Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Bin Zhang
Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Walsh Martin
Department of Pharmacological Sciences, Center for RNA Biology and Medicine, New York, NY, 10029, USA.
Friedel Roland H
ORCID
Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Zaslavsky Elena
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Tsankova Nadejda M
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
[email protected]. | Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
[email protected].
