Abstract 18239: Yy1 Expression is Sufficient for the Mantenance of Cardiac Progenitor Cell State
BACKGROUND: Transcription factors and epigenetic modifiers regulate gene expression during cardiac development. We have previously shown that YY1 is essential for the commitment of mesodermal precursors into cardiac progenitor cells (CPCs); however, the role of YY1 in the maintenance of CPC phenotype and their differentiation into cardiomyocytes is unknown.
METHODS AND RESULTS: We performed genome-wide expression analysis and targeted real-time qPCR as well as chromatin immunoprecipitation assays for histone modification in mouse embryonic stem cell (ESC)-derived CPCs with and without YY1 over-expression. We found, by genome-wide transcriptional profiling and phenotypic assays, that YY1 overexpression prevents cardiomyogenic differentiation and maintains the proliferative capacity of CPCs. We show further that the ability of YY1 to regulate CPC phenotype is associated with its ability to modulate histone modifications specifically at a developmentally critical enhancer of Nkx2-5 and other key cardiac transcription factors such as Tbx5. Specifically, YY1 overexpression promotes the maintenance of markers of gene activation, such as the acetylation of histone H3 at lysine 9 (H3K9Ac) and lysine 27 (H3K27Ac), as well as trimethylation at lysine 4 (H3K4Me3) at the Nkx2-5 cardiac enhancer. Furthermore, transcription factors associated proteins such as PoII, p300, and Brg1 are also enriched at the Nkx2-5 enhancer with YY1 overexpression. The biological activities of YY1 in CPCs appear to be cell-autonomous, based on co-culture assays in differentiating CPCs that over-express YY1.
CONCLUSION: These results demonstrate that YY1 expression is sufficient to maintain a CPC phenotype through its ability to sustain the presence of activating epigenetic and chromatin marks at key cardiac enhancers.
Author Disclosures: G. Li: None. S. Gregoire: None. A. Sturzu: None. R. Schwartz: None. S. Wu: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.