YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed....
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/13/6649 |
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| author | Yunan Gao Yan Sun Adife Gulhan Ercan-Sencicek Justin S. King Brynn N. Akerberg Qing Ma Maria I. Kontaridis William T. Pu Zhiqiang Lin |
| author_facet | Yunan Gao Yan Sun Adife Gulhan Ercan-Sencicek Justin S. King Brynn N. Akerberg Qing Ma Maria I. Kontaridis William T. Pu Zhiqiang Lin |
| author_sort | Yunan Gao |
| collection | DOAJ |
| description | Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr3</i>, <i>Tlr4</i>, <i>Tlr5</i>, <i>Tlr6</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac <i>Tlr3</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> increased with age between neonatal and adult developmental stages, whereas the expression of <i>Tlr5</i> decreased with age. Furthermore, pathological stress increased the expression levels of <i>Tlr2</i>, <i>Tlr4</i>, <i>Tlr5</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i>. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr3</i>, <i>Tlr4</i>, <i>Tlr5</i>, <i>Tlr6</i>, <i>Tlr7</i>, and <i>Tlr9</i>. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of <i>Tlr4</i> depends on a conserved TEAD1 binding motif near <i>Tlr4</i> transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes. |
| first_indexed | 2024-03-10T10:12:11Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:12:11Z |
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| spelling | doaj.art-f32e77e5ebb7447b97b04d4df48413582023-11-22T01:08:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012213664910.3390/ijms22136649YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor GenesYunan Gao0Yan Sun1Adife Gulhan Ercan-Sencicek2Justin S. King3Brynn N. Akerberg4Qing Ma5Maria I. Kontaridis6William T. Pu7Zhiqiang Lin8Masonic Medical Research Institute, 2150 Bleecker St, Utica, NY 13501, USAMasonic Medical Research Institute, 2150 Bleecker St, Utica, NY 13501, USAMasonic Medical Research Institute, 2150 Bleecker St, Utica, NY 13501, USADepartment of Cardiology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USADepartment of Cardiology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USADepartment of Cardiology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USAMasonic Medical Research Institute, 2150 Bleecker St, Utica, NY 13501, USADepartment of Cardiology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USAMasonic Medical Research Institute, 2150 Bleecker St, Utica, NY 13501, USAToll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr3</i>, <i>Tlr4</i>, <i>Tlr5</i>, <i>Tlr6</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac <i>Tlr3</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> increased with age between neonatal and adult developmental stages, whereas the expression of <i>Tlr5</i> decreased with age. Furthermore, pathological stress increased the expression levels of <i>Tlr2</i>, <i>Tlr4</i>, <i>Tlr5</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i>. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr3</i>, <i>Tlr4</i>, <i>Tlr5</i>, <i>Tlr6</i>, <i>Tlr7</i>, and <i>Tlr9</i>. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of <i>Tlr4</i> depends on a conserved TEAD1 binding motif near <i>Tlr4</i> transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes.https://www.mdpi.com/1422-0067/22/13/6649YAPTEAD1Toll-like receptorheartTLR4cardiomyocyte |
| spellingShingle | Yunan Gao Yan Sun Adife Gulhan Ercan-Sencicek Justin S. King Brynn N. Akerberg Qing Ma Maria I. Kontaridis William T. Pu Zhiqiang Lin YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes International Journal of Molecular Sciences YAP TEAD1 Toll-like receptor heart TLR4 cardiomyocyte |
| title | YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes |
| title_full | YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes |
| title_fullStr | YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes |
| title_full_unstemmed | YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes |
| title_short | YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes |
| title_sort | yap tead1 complex is a default repressor of cardiac toll like receptor genes |
| topic | YAP TEAD1 Toll-like receptor heart TLR4 cardiomyocyte |
| url | https://www.mdpi.com/1422-0067/22/13/6649 |
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