SOX9 modulates the expression of key transcription factors required for heart valve development
Abstract
Heart valve formation initiates when endothelial cells of the heart transform into mesenchyme and populate the cardiac cushions. The transcription factor SOX9 is highly expressed in the cardiac cushion mesenchyme, and is essential for heart valve development. Loss of Sox9 in mouse cardiac cushion mesenchyme alters cell proliferation, embryonic survival, and valve formation. Despite this important role, little is known about how SOX9 regulates heart valve formation or its transcriptional targets. Therefore, we mapped putative SOX9 binding sites by ChIP-Seq in E12.5 heart valves, a stage at which the valve mesenchyme is actively proliferating and initiating differentiation. Embryonic heart valves have been shown to express a high number of genes that are associated with chondrogenesis, including several extracellular matrix proteins and transcription factors that regulate chondrogenesis. Therefore, we compared regions of putative SOX9 DNA binding between E12.5 heart valves and E12.5 limb buds. We identified context-dependent and context-independent SOX9-interacting regions throughout the genome. Analysis of context-independent SOX9 binding suggests an extensive role for SOX9 across tissues in regulating proliferation-associated genes including key components of the AP-1 complex. Integrative analysis of tissue-specific SOX9-interacting regions and gene expression profiles on Sox9-deficient heart valves demonstrated that SOX9 controls the expression of several transcription facto…
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EndMT is controlled by transcription factors including SNAI2, GATA4, and SOX9, activated in response to cues including TGFβ, WNT, and NOTCH.
“This transdifferentiation event is controlled by various transcription factors, like SNAI214, GATA415, and SOX916,17, which are activated in response to cues from neighbouring cell types, including the TGFβ superfamily9,10, WNT18, and NOTCH19,20.”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [16]
SOX9 is critical for AV valve development, including EndMT and matrix remodelling.
“SOX9 is critical for AV valve development, including in EndMT and matrix remodelling16,17,51,52”
From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [16]
During cardiac valve development, SOX9 is essential during cushion formation, which involves EndMT, and SOX9 activates transcription of key regulators of heart valve development.
“During cardiac valve development, SOX9 is essential during cushion formation, which involves EndMT, and where SOX9 activates transcription of key regulators of heart valve development (11,17).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [17]
SOX9 acts as a master regulator in heart valve development, binding regulatory regions that control TFs important for proper valve development, but its impact on the chromatin landscape is not yet characterized.
“SOX9 acts as a master regulator in heart valve development, binding regulatory regions that control TFs important for proper valve development, but its impact on the chromatin landscape is not yet characterized (17).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [17]
SOX9 acts as a master regulator.
“highlighting the role of SOX9 as a master regulator (17,54,55).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [17]
The identified SOX motifs are similar to previously identified motifs for SOX9.
“which are similar to previously identified motifs for SOX9 (5,17,53,62).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [17]
In mouse, SOX9 is essential in skin wound healing.
“Previous work in mouse has shown that SOX9 is essential for the EndMT process that produces functioning heart valves, as well as in skin wound healing, and acts as a master TF (11,16,17,66).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [17]
In mouse, SOX9 is essential for the EndMT process that produces functioning heart valves.
“Previous work in mouse has shown that SOX9 is essential for the EndMT process that produces functioning heart valves, as well as in skin wound healing, and acts as a master TF (11,16,17,66).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [17]
Previous studies found that 20-30% of SOX9 bound regions occurred within TSS/proximal promoter sites in developing mouse heart valves, limbs, and chondrocytes.
“Previous studies of genome-wide chromatin binding by SOX9 found that 20–30% of SOX9 bound regions occurred within TSS/proximal promoter sites in developing mouse heart valves, limbs, and chondrocytes (17,62).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [17]
Cites
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EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.
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Self-citationEssential role of Sox9 in the pathway that controls formation of cardiac valves and septa
Akiyama, H., Chaboissier, M.-C., Behringer, R. R., Rowitch, D. H., Schedl, A., Epstein, J. A., & de Crombrugghe, B. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401711101 · Cited by 265 · see citing works
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Self-citationCai, X., Zhang, W., Hu, J., Zhang, L., Sultana, N., Wu, B., Cai, W., Zhou, B., & Cai, C.-L. (2013) · Development · doi:10.1242/dev.092502 · Cited by 75 · see citing works
Hou, J., Charters, A. M., Lee, S. C., Zhao, Y., Wu, M. K., Jones, S. J., Marra, M. A., & Hoodless, P. A. (2007) · BMC Developmental Biology · doi:10.1186/1471-213x-7-92 · Cited by 56 · cited 1× · see citing works
“In situ hybridization was performed as described (Hou et al., 2007).”
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Liu, C.-F., Angelozzi, M., Haseeb, A., & Lefebvre, V. (2018) · Development · doi:10.1242/dev.164459 · Cited by 73 · see citing works
SOX9 reprograms endothelial cells by altering the chromatin landscape
Fuglerud, B. M., Drissler, S., Lotto, J., Stephan, T. L., Thakur, A., Cullum, R., & Hoodless, P. A. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac652 · Cited by 35 · see citing works
“During cardiac valve development, SOX9 is essential during cushion formation, which involves EndMT, and where SOX9 activates transcription of key regulators of heart valve development (11,17).”
BackgroundResultInfluentialSelf-citationCell diversity and plasticity during atrioventricular heart valve EMTs
Lotto, J., Cullum, R., Drissler, S., Arostegui, M., Garside, V. C., Fuglerud, B. M., Clement-Ranney, M., Thakur, A., Underhill, T. M., & Hoodless, P. A. (2023) · Nature Communications · doi:10.1038/s41467-023-41279-6 · Cited by 13 · see citing works
“The three AV mesenchymal populations all express regulators of mesenchymal identity, such as Sox9 16 , Msx1 40 , and Tbx20 41 , but differ in timepoint composition or proliferative status (Fig.”
BackgroundSelf-citation
- Authors
- Garside, V. C., Cullum, R., Alder, O., Lu, D. Y., Vander Werff, R., Bilenky, M., Zhao, Y., Jones, S. J. M., Marra, M. A., Underhill, T. M., & Hoodless, P. A.
- Affiliations
- BC Cancer Agency (CA)
- Biomedical Research Centre, University of British Columbia, Vancouver, V6T1Z4, Canada
- University of British Columbia (CA)
- Corresponding author
- Hoodless, Pamela A.
- ORCID
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2015-01-01
- Volume
- 142
- Issue
- 24
- Pages
- 4340-50
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2342847661
- Cited by
- 65
- References
- 8
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 7 · 2019: 10 · 2018: 7 · 2017: 7 · 2016: 3
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- SOX9, heart valve development, transcriptional regulation, ChIP-seq, chondrogenesis, cell proliferation, TWIST1, SOX4, MECOM, PITX2, AP-1 complex, limb bud, transcriptional hierarchy
- MeSH terms
- Animals, DNA, Extremities, Heart Valves, Models, Biological, Promoter Regions, Genetic, Protein Binding, RNA, Messenger, Gene Expression Regulation, Developmental, Transcription Initiation Site, Chromatin Immunoprecipitation, Cell Proliferation, Mice, Gene Regulatory Networks, SOX9 Transcription Factor
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