Project description:The following abstract from the submitted manuscript describes the major findings of this work. The metabolic development of high energy-utilizing organs such as the heart involves mitochondrial proliferation at birth followed by a maturation process during the postnatal period. Conditional gene targeting was used in mice to explore the role of the PPARgamma coactivator 1 (PGC-1) coactivators during postnatal development and in adult heart. Marked mitochondrial derangements were observed in hearts of PGC-1a/b-deficient mice during the postnatal period, including fragmentation and elongation associated with the development of a lethal cardiomyopathy. The expression of multiple genes involved in mitochondrial fusion and fission was downregulated in hearts of PGC-1a/b-deficient mice. PGC-la was shown to activate transcription of the mitofusin 1 (Mfn1) gene by coactivating the estrogen-related receptor a (ERRa) upon a highly conserved element. Surprisingly, PGC-1a/b deficiency did not alter cardiac function or general mitochondrial density and myocyte distribution in adult heart. However, transcriptional profiling and mitochondrial function studies demonstrated that the PGC-1 coactivators are required for full respiratory capacity and high level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial energy transduction and oxidative phosphorylation pathways in adult heart. These results unveil distinct developmental stage-specific transcriptional programs involved in the maturation and maintenance of mitochondria. RNA from five PGC-1a-/- and five PGC-1a-/-bf/f/MerCre mice was analyzed.
Project description:The following abstract from the submitted manuscript describes the major findings of this work. The metabolic development of high energy-utilizing organs such as the heart involves mitochondrial proliferation at birth followed by a maturation process during the postnatal period. Conditional gene targeting was used in mice to explore the role of the PPARgamma coactivator 1 (PGC-1) coactivators during postnatal development and in adult heart. Marked mitochondrial derangements were observed in hearts of PGC-1a/b-deficient mice during the postnatal period, including fragmentation and elongation associated with the development of a lethal cardiomyopathy. The expression of multiple genes involved in mitochondrial fusion and fission was downregulated in hearts of PGC-1a/b-deficient mice. PGC-la was shown to activate transcription of the mitofusin 1 (Mfn1) gene by coactivating the estrogen-related receptor a (ERRa) upon a highly conserved element. Surprisingly, PGC-1a/b deficiency did not alter cardiac function or general mitochondrial density and myocyte distribution in adult heart. However, transcriptional profiling and mitochondrial function studies demonstrated that the PGC-1 coactivators are required for full respiratory capacity and high level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial energy transduction and oxidative phosphorylation pathways in adult heart. These results unveil distinct developmental stage-specific transcriptional programs involved in the maturation and maintenance of mitochondria.
Project description:Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown. The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive marks during development that persist into adulthood, but its function in postnatal organ homeostasis is unknown. We show that Ezh2 stabilizes cardiac gene expression and prevents cardiac pathology by repressing the homeodomain transcription factor Six1, which functions in cardiac progenitors but is stably silenced upon cardiac differentiation. Ezh2 deletion in cardiac progenitors caused postnatal myocardial pathology and destabilized cardiac gene expression with activation of Six1-dependent skeletal muscle genes. Six1 induced cardiomyocyte hypertrophy and skeletal muscle gene expression. Furthermore, genetically reducing Six1 levels rescued the pathology of Ezh2-deficient hearts. Thus, Ezh2-mediated repression of Six1 in differentiating cardiac progenitors is essential for stable postnatal heart gene expression and homeostasis. Our results suggest that epigenetic dysregulation in embryonic progenitor cells predisposes to adult disease and dysregulated stress responses. Four samples were analyzed. RNA was obtained from ventricles from two wild type and two Ezh2-deficient hearts.
Project description:Our study has two main goals. The first is to define a gene expression atlas of heart valve cells and identify cell heterogeneity within postnatal heart valve development. The second is to identify interstitial cell populations involved in ECM remodeling during postnatal heart valve development.