Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma

Jessica Tome-Garcia, Parsa Erfani, German Nudelman, Alexander M. Tsankov, Igor Katsyv, Rut Tejero, Zhang, Martin Walsh, Roland H. Friedel, Elena Zaslavsky and Nadejda M. Tsankova ()
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Jessica Tome-Garcia: Icahn School of Medicine at Mount Sinai
Parsa Erfani: Icahn School of Medicine at Mount Sinai
German Nudelman: Icahn School of Medicine at Mount Sinai
Alexander M. Tsankov: Broad Institute of MIT and Harvard
Igor Katsyv: Icahn School of Medicine at Mount Sinai
Rut Tejero: Icahn School of Medicine at Mount Sinai
Zhang: Icahn School of Medicine at Mount Sinai
Martin Walsh: Center for RNA Biology and Medicine
Roland H. Friedel: Icahn School of Medicine at Mount Sinai
Elena Zaslavsky: Icahn School of Medicine at Mount Sinai
Nadejda M. Tsankova: Icahn School of Medicine at Mount Sinai

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06258-2

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