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Stage-specific Chromatin Modification and Regulation in Cardiomyocyte Differentiation

  • Author(s): Alexander, Jeffrey M.
  • Advisor(s): Bruneau, Benoit G
  • et al.
Abstract

Development of a properly formed heart is vital to life and defects in cardiogenesis lead to congenital heart disease. Central to this process is the commitment and differentiation of cardiovascular cell types from pluripotent progenitors, which depends on activation of entire gene expression programs. Chromatin structure is essential for the modulation of gene expression, yet we know little about how chromatin is modified and regulated during cardiogenesis. We have described the changing chromatin landscape of cardiac differentiation and investigated how chromatin regulators, such as chromatin remodelers, impact gene expression during this process. Using an efficient directed differentiation of cardiomyocytes from embryonic stem cells, we identified four stages of cardiac differentiation and profiled genome-wide occupancy of histone modifications. We found multiple, distinct chromatin patterns and have demonstrated the relationship between these patterns and gene expression. In addition, we identified a novel pre-activation chromatin pattern found at many cardiac muscle genes. Using histone modification signature, we have identified numerous putative enhancer regions, which allowed for the discovery of novel transcriptional regulatory networks and the identification of transcriptional synergism between the transcription factors Gata4 and Meis1. Furthermore, we studied the role of the chromatin remodeling factor, Brg1, in cardiac differentiation. We determined that Brg1 is required for cardiac differentiation and early loss of Brg1 led to the derepression of many Polycomb target genes. Further investigation revealed that Brg1 is required for H3K27me3 levels at many derepressed genes, suggesting a potential cooperativity between Brg1 and Polycomb repressive complexes. Taken together, our studies provide an important framework for future study of chromatin and its regulatory factors in the developing heart.

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