Browsing by Subject "Nuclear receptor"

Now showing 1 - 4 of 4
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    Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions
    (MDPI, 2019-10-11) Yan, Shengmin; Khambu, Bilon; Hong, Honghai; Liu, Gang; Huda, Nazmul; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of Medicine
    Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases.
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    Dynamic changes in P300 enhancers and enhancer-promoter contacts control mouse cardiomyocyte maturation
    (Elsevier, 2023) Zhou, Pingzhu; VanDusen, Nathan J.; Zhang, Yanchun; Cao, Yangpo; Sethi, Isha; Hu, Rong; Zhang, Shuo; Wang, Guangyu; Ye, Lincai; Mazumdar, Neil; Chen, Jian; Zhang, Xiaoran; Guo, Yuxuan; Li, Bin; Ma, Qing; Lee, Julianna Y.; Gu, Weiliang; Gupta, Weiliang; Yuan, Guo-Cheng; Ren, Bing; Chen, Kaifu; Pu, William T.; Pediatrics, School of Medicine
    Cardiomyocyte differentiation continues throughout murine gestation and into the postnatal period, driven by temporally regulated expression changes in the transcriptome. The mechanisms that regulate these developmental changes remain incompletely defined. Here, we used cardiomyocyte-specific ChIP-seq of the activate enhancer marker P300 to identify 54,920 cardiomyocyte enhancers at seven stages of murine heart development. These data were matched to cardiomyocyte gene expression profiles at the same stages and to Hi-C and H3K27ac HiChIP chromatin conformation data at fetal, neonatal, and adult stages. Regions with dynamic P300 occupancy exhibited developmentally regulated enhancer activity, as measured by massively parallel reporter assays in cardiomyocytes in vivo, and identified key transcription factor-binding motifs. These dynamic enhancers interacted with temporal changes of the 3D genome architecture to specify developmentally regulated cardiomyocyte gene expressions. Our work provides a 3D genome-mediated enhancer activity landscape of murine cardiomyocyte development.
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    Enhancing human cord blood hematopoietic stem cell engraftment by targeting nuclear hormone receptors
    (Wolters Kluwer, 2018-07) Guo, Bin; Huang, Xinxin; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    PURPOSE OF REVIEW: Allogeneic hematopoietic cell transplantation (HCT) is a life-saving therapy for hematological and nonhematological diseases. Cord blood is a source of transplantable hematopoietic stem cells (HSCs), but limited numbers of HSCs in single cord blood units, which may cause delayed neutrophil, platelet, and immune cell reconstitution, is a major problem for efficient transplantation. Ex-vivo expansion and enhanced homing of cord blood HSC may overcome this disadvantage and improve its long-term engraftment. Here, we discuss the role of nuclear hormone receptors signaling in human cord blood HSC engraftment. RECENT FINDINGS: Antagonizing retinoid acid receptor (RAR) signaling promotes human HSC expansion and increases myeloid cell production. Cord blood CD34 cells expanded by SR1 promotes efficient myeloid recovery after transplantation compared with control groups, and leads to successful engraftment. Short-term treatment of glucocorticoids enhances homing and long-term engraftment of human HSCs and HPCs in NSG mice. Peroxisome proliferator-activated receptor-γ (PPARγ) antagonism expands human HSCs and HPCs by preventing differentiation and enhancing glucose metabolism. These findings demonstrate that nuclear hormone receptor signaling components might be promising targets for improving human cord blood HCT. SUMMARY: Better understanding of molecular mechanisms underlying human HSC expansion and homing mediated by nuclear hormone receptor signaling pathways will facilitate enhanced HCT efficacy.
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    Upregulation of the ERRγ–VDAC1 axis underlies the molecular pathogenesis of pancreatitis
    (National Academy of Science, 2023) Chanda, Dipanjan; Thoudam, Themis; Sinam, Ibotombi Singh; Lim, Chae Won; Kim, Myeongjin; Wang, Jiale; Lee, Kyeong-Min; Ma, Jing; Saxena, Romil; Choi, Jinhyuk; Oh, Chang Joo; Lee, Hoyul; Jeon, Yong Hyun; Cho, Sung Jin; Jung, Hoe-Yune; Park, Keun-Gyu; Choi, Hueng-Sik; Suh, Jae Myoung; Auwerx, Johan; Ji, Baoan; Liangpunsakul, Suthat; Jeon, Jae-Han; Lee, In-Kyu; Medicine, School of Medicine
    Emerging evidence suggest that transcription factors play multiple roles in the development of pancreatitis, a necroinflammatory condition lacking specific therapy. Estrogen-related receptor γ (ERRγ), a pleiotropic transcription factor, has been reported to play a vital role in pancreatic acinar cell (PAC) homeostasis. However, the role of ERRγ in PAC dysfunction remains hitherto unknown. Here, we demonstrated in both mice models and human cohorts that pancreatitis is associated with an increase in ERRγ gene expression via activation of STAT3. Acinar-specific ERRγ haploinsufficiency or pharmacological inhibition of ERRγ significantly impaired the progression of pancreatitis both in vitro and in vivo. Using systematic transcriptomic analysis, we identified that voltage-dependent anion channel 1 (VDAC1) acts as a molecular mediator of ERRγ. Mechanistically, we showed that induction of ERRγ in cultured acinar cells and mouse pancreata enhanced VDAC1 expression by directly binding to specific site of the Vdac1 gene promoter and resulted in VDAC1 oligomerization. Notably, VDAC1, whose expression and oligomerization were dependent on ERRγ, modulates mitochondrial Ca2+ and ROS levels. Inhibition of the ERRγ-VDAC1 axis could alleviate mitochondrial Ca2+ accumulation, ROS formation and inhibit progression of pancreatitis. Using two different mouse models of pancreatitis, we showed that pharmacological blockade of ERRγ-VDAC1 pathway has therapeutic benefits in mitigating progression of pancreatitis. Likewise, using PRSS1R122H-Tg mice to mimic human hereditary pancreatitis, we demonstrated that ERRγ inhibitor also alleviated pancreatitis. Our findings highlight the importance of ERRγ in pancreatitis progression and suggests its therapeutic intervention for prevention and treatment of pancreatitis.