Cardiac development, growth, and disease through chromatin remodeling
- Calvin Tyi Hang.
- June 2011.
- Physical description
- online resource (ix, 155 pages) : illustrations (some color)
- Hang, Calvin Tyi.
- Chang, Ching-Pin. thesis advisor (primary).
- Cleary, Michael L. thesis advisor.
- Crabtree, Gerald R. thesis advisor.
- Kuo, Calvin Jay. thesis advisor.
- Stanford University. Program in Cancer Biology.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references (p. 144-155). 170 refs.
- The heart is the first organ to function in development and continues to beat for seventy or more years in an adult's life. Cardiogenesis therefore is no simple task; genes have to be precisely regulated to meet the needs of a developing heart. ATP-dependent chromatin remodeling provides an important mechanism to regulate gene expression. Specifically, Brg1-associated factor, or the BAF, complexes, are crucial in heart development. Endocardial Brg1 represses the expression of a metalloproteinase, ADAMTS1, in order to allow sufficient cardiac jelly expansion for trabecular development. In addition, Brg1 functions in the myocardium to repress VEGFA to prevent the ectopic formation of coronary vasculature from the epicardium in a non-cell autonomous manner. And lastly, Brg1 serves as a bridge linking embryonic development and adult cardiomyopathies. Brg1 functions in the myocardium to keep the cardiomyocytes in a proliferating state through promoting BMP10 and repressing a cyclin-dependent kinase inhibitor p57kip2. Without Brg1, cardiomyocytes cease cell division, mature, and express adult form of myosin heavy (MHC) chain gene. Brg1 is normally turned off in adult life; however, following cardiac stress it is reactivated and turns on embryonic fetal program characterized by re-induction of embryonic MHC expression. Preventing Brg1 re-expression can repress cardiac hypertrophy and restore adult MHC expression. Furthermore, Brg1 physically interacts with other chromatin remodeling enzymes such as histone deacetylases and poly-ADP ribose polymerases to control expression of MHC genes and regulate cardiomyocyte differentiation. In all, ATP-dependent chromatin remodeling plays important roles in heart development and disease and may provide a suitable therapeutic target for human cardiomyopathies in the future.
- Publication date
- Submitted to the Program in Cancer Biology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2011.