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| Status |
Public on Aug 02, 2024 |
| Title |
Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors (ATAC-Seq) |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Long-term toxicities caused by cancer treatments have recently gained increasing recognition due to a steadily growing population of cancer survivors. Radiotherapy (RT) is a common treatment known to unintentionally harm surrounding normal tissues including the skin, hindering wound healing even years after treatment. Our study aimed to elucidate the underlying mechanisms of these late-onset adverse effects caused by RT. By comparing paired skin biopsies from previously irradiated (RT+) and non-irradiated (RT-) sites in breast cancer survivors who underwent RT years ago, we discovered compromised wound healing capacity and impaired fibroblast functions in the RT+ skin. By employing ATAC-seq, we identified altered chromatin landscapes in RT+ fibroblasts, pinpointing THBS1 as a crucial epigenetically primed wound repair-related gene. Further confirmation of THBS1's significance during wound repair came from single-cell RNA-sequencing and spatial transcriptomic analysis of human wounds. Remarkably, heightened and sustained THBS1 expression was observed in RT+ fibroblasts in both mouse and human radiation wound models, leading to impaired fibroblast motility and contractility. Encouragingly, our study found that treatment with anti-THBS1 antibodies promoted ex vivo wound closure in RT+ skin from breast cancer survivors. These findings indicate that dermal fibroblasts retain a long-term radiation memory recorded in the form of epigenetic changes. Targeting this maladaptive epigenetic memory shows promise for mitigating the late-onset adverse effects caused by RT, offering potential solutions to improve the quality of life for cancer survivors.
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| Overall design |
ATAC-seq was conducted on human skin fibroblasts isolated from both previously irradiated and non-irradiated areas of the same cancer patient, aiming to identify open chromatin regions across the genome. ATAC-seq was performed on human skin dermal fibroblasts treated with and without in vitro irradiation to identify open chromatin regions across the genome. ATAC-seq was performed on mouse dermal cells or fibroblasts isolated from irradiated or non-irradiated mice to identify open chromatin regions across the genome.
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| Contributor(s) |
Bian X, Piipponen M, Liu Z, Luo L, Landén NX |
| Citation(s) |
39468077 |
| |
| Submission date |
Jan 31, 2024 |
| Last update date |
Nov 01, 2024 |
| Contact name |
Ning Xu Landén |
| E-mail(s) |
[email protected]
|
| Phone |
+46 (0)762345626
|
| Organization name |
Karolinska Institutet
|
| Street address |
K2 Medicin, Solna, K2 Derm o Ven Xu Landén N
|
| City |
Stockholm |
| ZIP/Postal code |
171 77 |
| Country |
Sweden |
| |
|
| Platforms (3) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
| GPL34284 |
Illumina NovaSeq X Plus (Homo sapiens) |
| GPL34290 |
Illumina NovaSeq X Plus (Mus musculus) |
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| Samples (45)
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| Relations |
| BioProject |
PRJNA1071623 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE254753_Ctr_D14_1.zip |
6.1 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Ctr_D14_2.zip |
5.9 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Ctr_D14_3.zip |
6.0 Mb |
(ftp)(http) |
ZIP |
| GSE254753_IR_D14_1.zip |
4.9 Mb |
(ftp)(http) |
ZIP |
| GSE254753_IR_D14_2.zip |
4.9 Mb |
(ftp)(http) |
ZIP |
| GSE254753_IR_D14_3.zip |
5.3 Mb |
(ftp)(http) |
ZIP |
| GSE254753_IRvsCtrl_macs3_processed_data.zip |
37.4 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_Ctr_dermal_cell_D7-1.zip |
4.1 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_Ctr_dermal_cell_D7-2.zip |
4.4 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_Ctr_dermal_cell_D7-3.zip |
4.4 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_Ctr_dermal_fibroblasts_D1-1.zip |
4.2 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_Ctr_dermal_fibroblasts_D1-2.zip |
4.8 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_IR_dermal_cell_D7-1.zip |
5.0 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_IR_dermal_cell_D7-2.zip |
4.6 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_IR_dermal_cell_D7-3.zip |
5.8 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_IR_dermal_fibroblasts_D1-1.zip |
4.4 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_IR_dermal_fibroblasts_D1-2.zip |
4.2 Mb |
(ftp)(http) |
ZIP |
| GSE254753_Mm_IR_dermal_fibroblasts_D1-3.zip |
4.7 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS17_RT_macs3.zip |
4.1 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS17_nonRT_macs3.zip |
4.6 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS26_RT_macs3.zip |
4.7 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS26_nonRT_macs3.zip |
4.8 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS2_RT_macs2.zip |
4.6 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS2_nonRT_macs2.zip |
4.5 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS3_RT_macs2.zip |
4.5 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS3_nonRT_macs2.zip |
4.4 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS47_RT-S+.zip |
6.0 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS47_RT-S-.zip |
5.7 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS48RT-S+.zip |
5.5 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS48_RT-S-.zip |
5.9 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS49RT-S+.zip |
5.5 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS49RT-S-.zip |
5.8 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS4_RT_macs2.zip |
3.3 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS4_nonRT_macs2.zip |
3.4 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS5_RT_macs2.zip |
2.6 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS5_nonRT_macs2.zip |
4.1 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS6_RT_macs2.zip |
2.4 Mb |
(ftp)(http) |
ZIP |
| GSE254753_RS6_nonRT_macs2.zip |
2.9 Mb |
(ftp)(http) |
ZIP |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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