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| Status |
Public on Sep 26, 2019 |
| Title |
Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Histone H3 lysine 27 to methionine mutations (H3K27M) resulting in aberrant chromatin regulation are frequently observed in Diffuse Intrinsic Pontine Glioma (DIPG), a pediatric brain tumor with no cure. We conducted a CRISPR screen to determine if various chromatin regulators might be targeted to treat DIPG. Excitingly, this genetic screen reveals that co-targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) results in an enhanced growth suppressive effect in patient DIPG cells. Consistent with the genetic screen, a bifunctional inhibitor of HDACs and LSD1, Corin, inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin rescues H3K27me3 levels typically suppressed by the dominant effects of H3K27M mutations in DIPG and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at enhancers. Further studies reveal that Corin de-regulates DIPG transcription resulting in cell death, cell cycle arrest, and the induction of neuronal differentiation. These data suggest that co-targeting LSD1 and HDACs may represent a novel strategy for treating DIPG.
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| Overall design |
RNA-seq of polyA RNA from SU-DIPGXIII cells that had been treated with 0.5 uM of the LSD1 inhibitor, JKD-1-62, the HDAC inhibitor MS-275, the dual LSD1 and HDAC inhibitor, Corin, or the vehicle control, DMSO.
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| |
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| Contributor(s) |
Anastas J, Shi Y |
| Citation(s) |
31631026 |
| |
| Submission date |
Feb 13, 2018 |
| Last update date |
Jan 13, 2020 |
| Contact name |
Jamie Anastas |
| E-mail(s) |
jamie.anastas@childrens.harvard.edu, jamieanastas@gmail.com
|
| Phone |
16174298539
|
| Organization name |
Boston Children's Hospital
|
| Department |
Newborn Medicine
|
| Lab |
Yang Shi
|
| Street address |
300 Longwood Ave
|
| City |
Boston, MA |
| State/province |
United States of America |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
|
| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE110572 |
Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG |
|
| Relations |
| BioProject |
PRJNA434042 |
| SRA |
SRP132895 |
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