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| Status |
Public on Sep 11, 2024 |
| Title |
FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma [Bisulfite-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Methylation profiling by high throughput sequencing
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| Summary |
The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of NKX2-1-negative LUAD to facilitate a gastric differentiation program. Using sequential recombination models, we find that FoxA1/2 are required for demethylation of gastric-defining genes after Nkx2-1 deletion. FoxA1 colocalizes with TET3, an enzyme that mediates DNA demethylation, in NKX2-1-negative tumors. Deletion of Foxa1/2 results in loss of TET3 occupancy at key gastric marker genes, indicating that FoxA1/2 recruit TET3 to lineage-specific sites. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of enhancers and promoters as well as their 3D interactions at gastric target genes following NKX2-1 loss. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming in NKX2-1-negative LUAD. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.
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| Overall design |
To identify the FoxA1/2- and KRAS-dependent methylation changes, enzymatic methyl-seq was performed on sorted GFP+, DAPI+ tumor nuclei from each GEMM (K, KN, KNF1F2, N)
To determine whether FoxA1/2 were required to maintain methylation patterns in a gastric differentiation program, enzymatic methyl-seq was performed on 3D organoid lines, KG1A and 22E, in the presence and absence of FoxA1/2.
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| Contributor(s) |
Fort G, Orellana W |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Nov 15, 2023 |
| Last update date |
Sep 21, 2024 |
| Contact name |
Katherine Gillis |
| E-mail(s) |
[email protected]
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| Phone |
3013955164
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| Organization name |
Snyder Lab at Huntsman Cancer Institute
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| Street address |
2000 CIRCLE OF HOPE DR
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| City |
Salt Lake City |
| State/province |
UT |
| ZIP/Postal code |
84112-5550 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (29)
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| GSM7901564 |
KN tumors, replicate methyl-seq 1 |
| GSM7901565 |
KN tumors, replicate methyl-seq 2 |
| GSM7901566 |
KN tumors, replicate methyl-seq 3 |
| GSM7901567 |
KNF1F2 tumors, replicate methyl-seq 1 |
| GSM7901568 |
KNF1F2 tumors, replicate methyl-seq 2 |
| GSM7901569 |
KNF1F2 tumors, replicate methyl-seq 3 |
| GSM7901570 |
N neoplasias, replicate methyl-seq 1 |
| GSM7901571 |
N neoplasias, replicate methyl-seq 2 |
| GSM7901572 |
N neoplasias, replicate methyl-seq 3 |
| GSM7901573 |
22E-EtOH replicate methyl-seq 1 |
| GSM7901574 |
22E-EtOH replicate methyl-seq 2 |
| GSM7901575 |
22E-4OHT replicate methyl-seq 1 |
| GSM7901576 |
22E-4OHT replicate methyl-seq 2 |
| GSM7901577 |
KG1A-EtOH replicate methyl-seq 1 |
| GSM7901578 |
KG1A-EtOH replicate methyl-seq 2 |
| GSM7901579 |
KG1A-4OHT replicate methyl-seq 1 |
| GSM7901580 |
KG1A-4OHT replicate methyl-seq 2 |
| GSM8524585 |
2 week KN tumor, replicate methyl-seq 1 |
| GSM8524586 |
2 week KN tumor, replicate methyl-seq 2 |
| GSM8524587 |
2 week KN tumor, replicate methyl-seq 3 |
| GSM8524588 |
7 day KN tumor, replicate methyl-seq 1 |
| GSM8524589 |
7 day KN tumor, replicate methyl-seq 2 |
| GSM8524590 |
7 day KN tumor, replicate methyl-seq 3 |
| GSM8524591 |
3 day KN tumor, replicate methyl-seq 1 |
| GSM8524592 |
3 day KN tumor, replicate methyl-seq 2 |
| GSM8524593 |
3 day KN tumor, replicate methyl-seq 3 |
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| This SubSeries is part of SuperSeries: |
| GSE247855 |
FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma |
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| Relations |
| BioProject |
PRJNA1040822 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE247853_RAW.tar |
6.3 Gb |
(http)(custom) |
TAR (of BW, COV) |
SRA Run Selector |
| Raw data are available in SRA |
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