Our goal is to define how nuclear hormone receptors modulate the structure, function and accessibility of the genome to control gene expression in prenatal development and postnatal physiology. The underlying hypothesis of this proposal is that receptor signaling is mediated by ligand-directed chromatin modifications and the resulting induced or repressed epigenetic states mobilize networks of genes in a temporal fashion to alter cell fate, function and physiology. To do this, in Aim I we will characterize a unique lung phenotype in which the disruption of Thyroid Hormone Receptor (TR) repression by the co-repressor SMRT results in neonatal lethality from a maturation defect in type I pneumocytes. We will correlate the immature lung phenotype at the anatomic and cellular level with de-repressed TR-dependent transcriptional signatures in fetal and perinatal lung, and in a cultured pneumocyte cell line (MLE-12) that is thyroid hormone responsive and expresses TR and Type I markers. The recent availability of massively parallel sequencing technology and advances in methods for chromatin immunoprecipitation now makes it possible to determine the specific genomic locations (cistrome) of SMRT and TR on a genome wide scale.
Aim II will determine the SMRT and TR cistromes in MLE-12 cells in the presence and absence of T3 by sequencing of ChIP products and mapping these to reference genomes.
Aim III will define the dynamics of epigenetic signatures during TR signaling in pneumocytic cells by mapping key histone acetylation and methylation markers in MLE-12 pneumocytes and primary cultured Type I cells derived from SMRTmRID mice. Integration of the results from Aims I- III will aid in understanding the molecular codes that underlie a specific and vital cell fate decision and provide new insights toward late gestational lung development and the prevention and treatment of infant respiratory diseases. In addition, much morbidity and mortality of the H1N1 flu is due to its infection and destruction of the type I pneumocyte. Our work and mouse model may provide new insights into type I pneumocyte protection and replenishment in susceptible human populations.
This proposal is directed at identifying how nuclear hormone receptors modulate the structure, function and accessibility of the genome to control gene expression in prenatal development and neo-natal physiology. Receptor regulated pathways are particularly relevant in fertility, congenital malformations, prematurity, and respiratory distress syndrome in the United States and this work is anticipated to provide insights for the development of new diagnostics and therapeutics.
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