Characterization of Baf60c in Mouse Heart Development

• Main Author: Sun, Xin
• Other Authors: Rossant, Janet
• Language: en_ca
• Published: 2012
• Online Access: http://hdl.handle.net/1807/32909

BAF (BRG1/Brm Associating Factors) complexes are ATP-dependent chromatin-remodeling complexes highly conserved from yeast to mammal. In mammals, the existence of tissue-specific BAF factors and their essential roles in the developmental processes suggest that they offer another layer of gene regulation control for mammalian development. Baf60c is one of the three Baf60s in the mouse. It expresses in the embryonic heart from E7.5 and later throughout the myocardium. To elucidate the role of Baf60c in mouse heart development, I constructed a Baf60c conditional knockout mouse line and characterize the Baf60c deletion phenotypes. Baf60c null embryonic hearts are hypoplastic and show abnormal contraction function and cardiomyocyte structural defects. Transcriptome analyses have identified gene groups critical for metabolism and contraction force generation. Deletion of Baf60c in myocardium at later development stages with Myh6::Cre results in severely dilated chambers, affecting the health and mortality. Echocardiography and electroncardiography have detected contraction and conduction defects in adult Baf60c myocardium deletion mice. Baf60c knockout cardiomyocyte also has disarrayed sarcomere. To elucidate the molecular mechanism by which Baf60c regulates cardiac gene expression, I detected the direct association of Baf60c with cardiac transcription factors Tbx5, Nkx2.5 and Myocardin. The transcription factor association domain is mapped to the N-terminal of Baf60c. To isolate the protein factors associated with Baf60c in vivo, I constructed a knock-in mouseline expressing epitope-tagged Baf60c. Expression of the tagged Baf60c was confirmed in ES cell differentiated cardiomyocyte and transgenic mice and its association with the other BAF complex members was also detected. In summary, my work has shown that the cardiac specific chromatin-remodeling factor Baf60c is an essential regulator for both embryonic heart and postnatal heart development. It may function through association with the cardiac transcription factors.