Transcription factors have been implicated in the development of congenital heart disease (CHD) emphasizing the importance of understanding how gene expression is regulated during early heart development. In addition to transcription factors, epigenetic regulation via histone modifications, chromatin remodeling and organization, and non-coding RNA are essential for mediating proper coordination of gene expression. CHD refers to abnormalities in the structure or function of the heart that arise during embryonic development and is the primary cause of infant morbidity worldwide. As CHD results from changes that occur early in development understanding the genetic and epigenetic mechanisms that coordinate cell fate decisions, tissue morphogenesis and cell lineage commitment during early cardiac development will be instrumental in elucidating the causes of CHD. Advances in high throughput sequencing technology have resulted in the unprecedented ability to define epigenetic and transcriptional landscapes on a genome-wide level and present a unique opportunity to elucidate the network of transcription factors, chromatin-related components and regulatory regions responsible for patterning the heart during embryogenesis. Using state of the art sequencing technology, we recently identified thousands of novel non-coding enhancer elements that are dynamically activated during cardiomyocyte differentiation and enriched for DNA binding motifs of stage specific transcription factors critical for heart development. Although enhancer regions are known to recruit transcription factors and interact with promoters, little is known about how transcription factor recruitment is coordinated with chromatin organization and state changes at enhancers to activate cell type specific gene expression during cardiogenesis. In light of this, the overall goal of this project is to determine how cis-regulatory regions, specifically enhancers, contribute to epigenetic control of gene expression during heart development. To accomplish this goal, in the mentored phase of the project, we will dissect the role of key cardiac transcription factors on establishment and maintenance of chromatin states in enhancer regions during in vitro cardiac differentiation. During the independent phase of the project, we will determine how long-range interactions between enhancer and promoter regions change during in vitro cardiac differentiation. Additionally, we will identify cell type specific cis-regulatory elements during in vivo cardiac development. This genome-wide analysis of enhancer regions during in vitro and in vivo cardiac development will provide crucial insights into how the regulatory architecture of vast non-coding portions of the genome impact gene expression programs necessary for patterning the developing heart.
Failure to properly regulate expression of genes during embryonic development can create severe abnormalities to the structure and function of the heart that result in congenital heart disease (CHD). As CHD is the leading cause of infant morbidity worldwide, the goal of this project is to determine how genes critical for cardiac development are controlled so we can better design therapeutic strategies to treat CHD and other cardiovascular diseases.
| O'Meara, Caitlin C; Wamstad, Joseph A; Gladstone, Rachel A et al. (2015) Transcriptional reversion of cardiac myocyte fate during mammalian cardiac regeneration. Circ Res 116:804-15 |
