Investigating Roles of the Brg1-Associated Factor (BAF) Chromatin Remodeling Complex during Mammalian Heart Valve Development
Datum
2016-02-23
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University of Oregon
Zusammenfassung
The integration of chromatin regulation into the gene regulatory networks that progressively transform endocardial cushions into highly structured valves is poorly understood. To investigate contributions of chromatin remodeling to valve development, we use two endocardial Cre lines to conditionally delete floxed Brg1, the core subunit of the Brg1-associated factor complex. In an early-deleting Tie2:Cre model, loss of Brg1 disrupts endocardial-mesenchymal transformation (EMT) in both the proximal outflow tract (pOFT) and atrioventricular canal (AVC) cushions. EMT appears to initiate normally in the absence of Brg1, but endocardial cells fail to switch from an epithelial to mesenchymal gene expression program. In a later-deleting Nfatc1Cre model, Brg1-deficient mice develop thickened, malpatterned and frequently bicuspid semilunar valves while showing normal AVC-derived valves. Fate mapping experiments demonstrate that the enlarged semilunar valves result from an expansion of non-Nfatc1Cre-lineage mesenchyme. Paradoxically, until E14.5, these same embryos have smaller semilunar valves, originating from a moderate deficiency of pOFT EMT. Depletion of this mesenchyme sub-population precludes formation of the valves’ base and hinge regions and disrupts growth regulatory networks, causing the valves to progress to a diseased state. RNA-seq of E14.5 Nfatc1Cre;Brg1F/F cardiac cushions identifies novel transcripts that may coordinate cellular interactions that direct growth and patterning stages of semilunar valve development. We propose that early disruption of EMT in the pOFT is sufficient to trigger secondary responses that culminate in commonly observed valve phenotypes in both mouse genetic models and human disease.
This dissertation includes previously published and unpublished co-authored material.