Endothelial deletion of INO80 disrupts coronary angiogenesis and causes congenital heart disease phenotypes
Abstract/Contents
- Abstract
- Organ size control is a vital developmental process that remains poorly understood. One example is the mammalian heart where the determinants that support ventricle wall expansion are not fully characterized. Defects in this developmental process directly contribute to congenital heart defects. For example, left ventricular non-compaction (LVNC) is a congenital heart defect in humans occurring when the compact myocardial layer does not expand properly during development, thus severely compromising heart muscle function. LVNC often requires heart transplantation, and if left untreated can result in heart failure. Despite its clinical significance, the mechanisms underlying LVNC are poorly understood. However, mutations in chromatin regulators have been found to be associated with several congenital heart defects, likely due to their important roles in regulating developmental gene expression programs. Interestingly, while the INO80 chromatin remodeler has demonstrated roles in genome stability, disease pathogenesis, and embryonic stem cell identity, there are currently no published studies detailing its function in mouse development. Our research demonstrates that the INO80 chromatin remodeler is required for proper cardiac development. Specifically, LVNC-like phenotypes arise when INO80 is deleted from the endothelial cells that line blood vessels, which correlated with defective coronary vascularization. Deletion of Ino80 individually in the two major coronary progenitors also resulted in non-compaction phenotypes. Mechanistically, loss of endothelial Ino80 resulted in increased E2F-mediated gene expression and proliferation potential, which suggests angiogenesis requires proliferation and that this process is critical in organ size control. Finally, our data suggests that providing two sources of blood vessels accelerates heart wall expansion and suppresses cardiac disease phenotypes.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2017; 2017 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Chung, Jae Ik |
|---|---|
| Degree supervisor | Morrison, Ashby J |
| Thesis advisor | Morrison, Ashby J |
| Thesis advisor | Bergmann, Dominique |
| Thesis advisor | Crabtree, Gerald R |
| Thesis advisor | Red-Horse, Kristy |
| Degree committee member | Bergmann, Dominique |
| Degree committee member | Crabtree, Gerald R |
| Degree committee member | Red-Horse, Kristy |
| Associated with | Stanford University, Department of Biology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Jae Ik Chung. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Jae Ik Chung
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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