SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis
SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 defic...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-02-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.154120 |
| _version_ | 1797634295520559104 |
|---|---|
| author | Yuchen Xie Merve Sahin Toru Wakamatsu Akane Inoue-Yamauchi Wanming Zhao Song Han Amrita M. Nargund Shaoyuan Yang Yang Lyu James J. Hsieh Christina S. Leslie Emily H. Cheng |
| author_facet | Yuchen Xie Merve Sahin Toru Wakamatsu Akane Inoue-Yamauchi Wanming Zhao Song Han Amrita M. Nargund Shaoyuan Yang Yang Lyu James J. Hsieh Christina S. Leslie Emily H. Cheng |
| author_sort | Yuchen Xie |
| collection | DOAJ |
| description | SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. Importantly, SETD2 loss sensitized KRAS-mutant lung cancer to inhibition of histone chaperones, the FACT complex, or transcriptional elongation both in vitro and in vivo. Overall, our studies not only provide insight into how SETD2 loss shapes the epigenetic and transcriptional landscape to promote tumorigenesis, but they also identify potential therapeutic strategies for SETD2 mutant cancers. |
| first_indexed | 2024-03-11T12:06:36Z |
| format | Article |
| id | doaj.art-609d7648d45a4ebb9f934f1c8a5d9339 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:36Z |
| publishDate | 2023-02-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-609d7648d45a4ebb9f934f1c8a5d93392023-11-07T16:25:15ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-02-0184SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesisYuchen XieMerve SahinToru WakamatsuAkane Inoue-YamauchiWanming ZhaoSong HanAmrita M. NargundShaoyuan YangYang LyuJames J. HsiehChristina S. LeslieEmily H. ChengSETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. Importantly, SETD2 loss sensitized KRAS-mutant lung cancer to inhibition of histone chaperones, the FACT complex, or transcriptional elongation both in vitro and in vivo. Overall, our studies not only provide insight into how SETD2 loss shapes the epigenetic and transcriptional landscape to promote tumorigenesis, but they also identify potential therapeutic strategies for SETD2 mutant cancers.https://doi.org/10.1172/jci.insight.154120Oncology |
| spellingShingle | Yuchen Xie Merve Sahin Toru Wakamatsu Akane Inoue-Yamauchi Wanming Zhao Song Han Amrita M. Nargund Shaoyuan Yang Yang Lyu James J. Hsieh Christina S. Leslie Emily H. Cheng SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis JCI Insight Oncology |
| title | SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis |
| title_full | SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis |
| title_fullStr | SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis |
| title_full_unstemmed | SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis |
| title_short | SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis |
| title_sort | setd2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis |
| topic | Oncology |
| url | https://doi.org/10.1172/jci.insight.154120 |
| work_keys_str_mv | AT yuchenxie setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT mervesahin setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT toruwakamatsu setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT akaneinoueyamauchi setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT wanmingzhao setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT songhan setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT amritamnargund setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT shaoyuanyang setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT yanglyu setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT jamesjhsieh setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT christinasleslie setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis AT emilyhcheng setd2regulateschromatinaccessibilityandtranscriptiontosuppresslungtumorigenesis |