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| Status |
Public on May 01, 2021 |
| Title |
Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [HiCHIP] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Heterogeneity between tumors is a major barrier to the treatment of small cell lung cancer (SCLC). Identification of molecular markers to characterize and classify tumors can facilitate the diagnosis and development of targeted therapies. Here, we analyzed genomic regions, called super enhancers (SE), across multiple SCLC cell lines and patient-derived xenograft models, and find SE enrichment is sufficient to classify SCLC models into recently defined SCLC molecular subtypes SCLC-A, SCLC-N, and SCLC-P defined by the transcription factors ASCL1, NEUROD1, and POU2F3, respectively. 3D chromatin structure analysis identified genes associated with the SE that assemble into subtype-specific tumor-signatures with genes functioning in diverse processes. Focusing on the SCLC-A subtype, transcription factors NKX2-1 and PROX1 were identified as ASCL1-interacting proteins. All three factors bind overlapping genomic regions within SEs in SCLC-A cell line models. Nevertheless, combined loss of all three factors suppresses growth of SCLC-A similar to that seen with ASCL1 loss alone, continuing to place ASCL1 as a key dependency factor in a subset of SCLC. Focusing on genes co-regulated by the three transcription factors, two SCLC-A subtype-specific cell surface proteins, SCN3A and KCNB2, were identified. Loss of either channel alone did not disrupt SCLC-A growth in vitro, but they may serve as diagnostic tools in subtyping SCLC.
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| Overall design |
HiChIP of H3K27ac to map enhancer-promoter loops in small cell lung cancer cell lines
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| Contributor(s) |
Pozo K, Kollipara RK, Zhang X, Johnson JE |
| Citation(s) |
34466783, 36325065 |
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| Submission date |
May 21, 2020 |
| Last update date |
Nov 17, 2022 |
| Contact name |
Jane E Johnson |
| E-mail(s) |
[email protected]
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| Organization name |
UT Southwestern Medical Center
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| Department |
Neuroscience
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| Street address |
5323 Harry Hines Blvd
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| City |
Dallas |
| State/province |
TX |
| ZIP/Postal code |
75390-9111 |
| Country |
USA |
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| Platforms (1) |
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| Samples (15)
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| This SubSeries is part of SuperSeries: |
| GSE151002 |
Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer |
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| Relations |
| BioProject |
PRJNA634353 |
| SRA |
SRP262645 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE151001_RAW.tar |
19.6 Mb |
(http)(custom) |
TAR (of BEDPE) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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