Bhlhe40 (also known as Stra13, Dec1, Sharp2, or BHLHB2) is a transcription factor that is highly induced by genotoxic stress and hypoxia, two conditions that are closely associated with exercise, in skeletal muscle (SKM) to protect this tissue from the harmful reactive oxygen species (ROS) associated with exercise. Unfortunately, the detailed mechanisms by which Bhlhe40 protect SKM from ROS induced damages have not been revealed yet. Peroxisomes are important metabolic organelles that participate in the β-oxidation of vary long chain, unsaturated, and branched fatty acids. Besides, antioxidant enzymes, including Catalase, SOD1, and PRDX5, localized in the peroxisomes are critical to the removal of the harmful ROS concomitantly generated from the oxidation of substrates in mitochondria (MITO) and peroxisomes. Both the number and functions of peroxisomes are highly regulated by the transcriptional coactivator PGC-1α. Both the number and functions of peroxisomes are highly regulated by the transcriptional coactivator PGC-1α. It has been shown that PGC-1α plays critical roles in the regulation of the biogenesis and function of mitochondria and peroxisomes through coactivating the activity of various DNA-binding transcription factors, such as PPARγ, ERRα, and NRF1. Our recent discovery showed that PGC-1α directly interacted with Bhlhe40 and they co-occupied PGC-1α targeted gene promoters/enhancers, which in turn repressed PGC-1α transactivational activity. Bhlhe40 repressed PGC-1α activity through HDACs recruitment and preventing the relief of PGC-1α intra-molecular repression. Unleashing this repression by knockdown of Bhlhe40 expression increased levels of ROS, fatty acid oxidation, mitochondria DNA, and the expression of PGC-1α target genes. Our preliminary results have further confirmed that Bhlhe40 does play important roles in regulating peroxisome functions and number. We found that both the number and activity of peroxisomes were increased upon knockdown of Bhlhe40 expression but were repressed by its over-expression. Over-expression of a constitutively active PGC-1α-interactive domain (named as VBH135) of Bhlhe40 mimicked the effects of its knockdown on peroxisomes but simultaneously reduced ROS level. Unsaturated fatty acid oxidation, insulin response, and oxidative respiration were highly enhanced in Bhlhe40 knockdown or VBH135 over-expressed cells, suggesting the importance of Bhlhe40 in the regulation of unsaturated fatty acid and glucose oxidative metabolism. Expression profiling of genes important for peroxisome function and biogenesis also supports the intimate regulation of peroxisomes by Bhlhe40. In this study, we will focus on delineating the regulatory mechanisms of peroxisome function and homeostasis by Bhlhe40 at molecular level in detail via dissecting the regulation of target genes by Bhlhe40 at genetic and epigenetic levels. The following experiments on Bhlhe40 targeted genes involved in peroxisome functions and homeostasis are proposed:1.Gain and loss of function effects on peroxisomes and myogenesis. 2.Cloning their promoters and cis-elements and characterizing their regulation by Bhlhe40.3.Examining the recruitment of Bhlhe40 and cofactors to these genes in vitro and in vivo.4.Analyzing their epigenetic modification and chromatin structure affected by Bhlhe40.
|Effective start/end date||1/08/18 → 31/07/19|
UN Sustainable Development Goals
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):
- skeletal muscle
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