Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses.
Smyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice usi...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4372598?pdf=render |
| _version_ | 1818416247470030848 |
|---|---|
| author | Tara L Rasmussen Yanlin Ma Chong Yon Park June Harriss Stephanie A Pierce Joseph D Dekker Nicolas Valenzuela Deepak Srivastava Robert J Schwartz M David Stewart Haley O Tucker |
| author_facet | Tara L Rasmussen Yanlin Ma Chong Yon Park June Harriss Stephanie A Pierce Joseph D Dekker Nicolas Valenzuela Deepak Srivastava Robert J Schwartz M David Stewart Haley O Tucker |
| author_sort | Tara L Rasmussen |
| collection | DOAJ |
| description | Smyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice using a knock-in (KI) Nkx2.5-cre driver. Robust deletion of floxed-Smyd1 in cardiomyocytes and the outflow tract (OFT) resulted in embryonic lethality at E9.5, truncation of the OFT and right ventricle, and additional defects consistent with impaired expansion and proliferation of the second heart field (SHF). Using a transgenic (Tg) Nkx2.5-cre driver previously shown to not delete in the SHF and OFT, early embryonic lethality was bypassed and both ventricular chambers were formed; however, reduced cardiomyocyte proliferation and other heart defects resulted in later embryonic death at E11.5-12.5. Proliferative impairment prior to both early and mid-gestational lethality was accompanied by dysregulation of transcripts critical for endoplasmic reticulum (ER) stress. Mid-gestational death was also associated with impairment of oxidative stress defense-a phenotype highly similar to the previously characterized knockout of the Smyd1-interacting transcription factor, skNAC. We describe a potential feedback mechanism in which the stress response factor Tribbles3/TRB3, when directly methylated by Smyd1, acts as a co-repressor of Smyd1-mediated transcription. Our findings suggest that Smyd1 is required for maintaining cardiomyocyte proliferation at minimally two different embryonic heart developmental stages, and its loss leads to linked stress responses that signal ensuing lethality. |
| first_indexed | 2024-12-14T11:47:51Z |
| format | Article |
| id | doaj.art-6474b35f28774de6a4df747fea3aeed0 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T11:47:51Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6474b35f28774de6a4df747fea3aeed02022-12-21T23:02:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e012176510.1371/journal.pone.0121765Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses.Tara L RasmussenYanlin MaChong Yon ParkJune HarrissStephanie A PierceJoseph D DekkerNicolas ValenzuelaDeepak SrivastavaRobert J SchwartzM David StewartHaley O TuckerSmyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice using a knock-in (KI) Nkx2.5-cre driver. Robust deletion of floxed-Smyd1 in cardiomyocytes and the outflow tract (OFT) resulted in embryonic lethality at E9.5, truncation of the OFT and right ventricle, and additional defects consistent with impaired expansion and proliferation of the second heart field (SHF). Using a transgenic (Tg) Nkx2.5-cre driver previously shown to not delete in the SHF and OFT, early embryonic lethality was bypassed and both ventricular chambers were formed; however, reduced cardiomyocyte proliferation and other heart defects resulted in later embryonic death at E11.5-12.5. Proliferative impairment prior to both early and mid-gestational lethality was accompanied by dysregulation of transcripts critical for endoplasmic reticulum (ER) stress. Mid-gestational death was also associated with impairment of oxidative stress defense-a phenotype highly similar to the previously characterized knockout of the Smyd1-interacting transcription factor, skNAC. We describe a potential feedback mechanism in which the stress response factor Tribbles3/TRB3, when directly methylated by Smyd1, acts as a co-repressor of Smyd1-mediated transcription. Our findings suggest that Smyd1 is required for maintaining cardiomyocyte proliferation at minimally two different embryonic heart developmental stages, and its loss leads to linked stress responses that signal ensuing lethality.http://europepmc.org/articles/PMC4372598?pdf=render |
| spellingShingle | Tara L Rasmussen Yanlin Ma Chong Yon Park June Harriss Stephanie A Pierce Joseph D Dekker Nicolas Valenzuela Deepak Srivastava Robert J Schwartz M David Stewart Haley O Tucker Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses. PLoS ONE |
| title | Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses. |
| title_full | Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses. |
| title_fullStr | Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses. |
| title_full_unstemmed | Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses. |
| title_short | Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses. |
| title_sort | smyd1 facilitates heart development by antagonizing oxidative and er stress responses |
| url | http://europepmc.org/articles/PMC4372598?pdf=render |
| work_keys_str_mv | AT taralrasmussen smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT yanlinma smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT chongyonpark smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT juneharriss smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT stephanieapierce smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT josephddekker smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT nicolasvalenzuela smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT deepaksrivastava smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT robertjschwartz smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT mdavidstewart smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses AT haleyotucker smyd1facilitatesheartdevelopmentbyantagonizingoxidativeanderstressresponses |