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#34341555   2021/08/02 To Up

Decoding disease: from genomes to networks to phenotypes.

Interpreting the effects of genetic variants is key to understanding individual susceptibility to disease and designing personalized therapeutic approaches. Modern experimental technologies are enabling the generation of massive compendia of human genome sequence data and associated molecular and phenotypic traits, together with genome-scale expression, epigenomics and other functional genomic data. Integrative computational models can leverage these data to understand variant impact, elucidate the effect of dysregulated genes on biological pathways in specific disease and tissue contexts, and interpret disease risk beyond what is feasible with experiments alone. In this Review, we discuss recent developments in machine learning algorithms for genome interpretation and for integrative molecular-level modelling of cells, tissues and organs relevant to disease. More specifically, we highlight existing methods and key challenges and opportunities in identifying specific disease-causing genetic variants and linking them to molecular pathways and, ultimately, to disease phenotypes.
Aaron K Wong, Rachel S G Sealfon, Chandra L Theesfeld, Olga G Troyanskaya

2146 related Products with: Decoding disease: from genomes to networks to phenotypes.

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#34332012   2021/07/28 To Up

Rare-earth nanoparticles induce depression, anxiety-like behavior, and memory impairment in mice.

Rare-earth nanoparticles have been widely studied for disease diagnosis, in vivo optical imaging, biosensing, and drug delivery. However, the effects of rare-earth nanoparticles on a central nervous system remain unclear. Here, we report that the continuous exposure to rare-earth nanoparticles in mice can cause behavioral alterations including cognitive deficits, anxiety, and depression-like behavior. Using an open-field test and a morris water maze, we showed that long-term exposure to rare-earth nanoparticles may lead to significant depression, anxiety-like behavior, and memory impairment. The histopathological investigation on the neurotoxicological effects of nanoparticles indicated a significant decrease in cell viability after seven days' nanoparticle exposure. Western blotting analysis suggested that the changes of ATP-citrate lyase (ACLY) and O-linked N-acetylglucosamine transferase (OGT, a unique glycosyltransferase enzyme) played important roles in neurobehavioral disorders in mice. These findings provide a pathway to understand the cytotoxicity of rare-earth nanoparticles for medial applications and offer insights into the risk of these nanoparticles in biological systems.
Caihou Lin, Guifen Liu, Yulong Huang, Shunyi Liu, Binghua Tang

1071 related Products with: Rare-earth nanoparticles induce depression, anxiety-like behavior, and memory impairment in mice.

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#34326778   2021/07/13 To Up

Skeletal Muscle O-GlcNAc Transferase Action on Global Metabolism Is Partially Mediated Through Interleukin-15.

Besides its roles in locomotion and thermogenesis, skeletal muscle plays a significant role in global glucose metabolism and insulin sensitivity through complex nutrient sensing networks. Our previous work showed that the muscle-specific ablation of O-GlcNAc transferase (OGT) led to a lean phenotype through enhanced interleukin-15 (IL-15) expression. We also showed OGT epigenetically modified and repressed the promoter. However, whether there is a causal relationship between OGT ablation-induced IL-15 secretion and the lean phenotype remains unknown. To address this question, we generated muscle specific OGT and interleukin-15 receptor alpha subunit (IL-15rα) double knockout mice (mDKO). Deletion of IL-15rα in skeletal muscle impaired IL-15 secretion. When fed with a high-fat diet, mDKO mice were no longer protected against HFD-induced obesity compared to wild-type mice. After 22 weeks of HFD feeding, mDKO mice had an intermediate body weight and glucose sensitivity compared to wild-type and OGT knockout mice. Taken together, these data suggest that OGT action is partially mediated by muscle IL-15 production and provides some clarity into how disrupting the O-GlcNAc nutrient signaling pathway leads to a lean phenotype. Further, our work suggests that interfering with the OGT-IL15 nutrient sensing axis may provide a new avenue for combating obesity and metabolic disorders.
Morgan D Zumbaugh, Con-Ning Yen, Jocelyn S Bodmer, Hao Shi, David E Gerrard

2204 related Products with: Skeletal Muscle O-GlcNAc Transferase Action on Global Metabolism Is Partially Mediated Through Interleukin-15.

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#34312767   2021/07/26 To Up

REM Sleep Deprivation Impairs Learning and Memory by Decreasing Brain O-GlcNAc Cycling in Mouse.

Rapid eye movement (REM) sleep is implicated learning and memory (L/M) functions and hippocampal long-term potentiation (LTP). Here, we demonstrate that REM sleep deprivation (REMSD)-induced impairment of contextual fear memory in mouse is linked to a reduction in hexosamine biosynthetic pathway (HBP)/O-GlcNAc flux in mouse brain. In mice exposed to REMSD, O-GlcNAcylation, and O-GlcNAc transferase (OGT) were downregulated while O-GlcNAcase was upregulated compared to control mouse brain. Foot shock fear conditioning (FC) induced activation of protein kinase A (PKA) and cAMP response element binding protein (CREB), which were significantly inhibited in brains of the REMSD group. Intriguingly, REMSD-induced defects in L/M functions and FC-induced PKA/CREB activation were restored upon increasing O-GlcNAc cycling with glucosamine (GlcN) or Thiamet G. Furthermore, Thiamet G restored the REMSD-induced decrease in dendritic spine density. Suppression of O-GlcNAcylation by the glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitor, 6-diazo-5-oxo-L-norleucine (DON), or OGT inhibitor, OSMI-1, impaired memory function, and inhibited FC-induced PKA/CREB activation. DON additionally reduced the amplitude of baseline field excitatory postsynaptic potential (fEPSP) and magnitude of long-term potentiation (LTP) in normal mouse hippocampal slices. To our knowledge, this is the first study to provide comprehensive evidence of dynamic O-GlcNAcylation changes during the L/M process in mice and defects in this pathway in the brain of REM sleep-deprived mice. Our collective results highlight HBP/O-GlcNAc cycling as a novel molecular link between sleep and cognitive function.
Sang-Min Kim, Seungjae Zhang, Jiwon Park, Hyun Jae Sung, Thuy-Duong Thi Tran, ChiHye Chung, Inn-Oc Han

2597 related Products with: REM Sleep Deprivation Impairs Learning and Memory by Decreasing Brain O-GlcNAc Cycling in Mouse.

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#34306413   2021/06/15 To Up

Analysis of the correlation of the expression level of hypoxia-inducible factor-1α with the glycosylation of oral squamous cell carcinoma.

To investigate the correlation of the expression level of hypoxia-inducible factor-1α (HIF-1α) with the glycosylation of oral squamous cell carcinoma (OSCC).
Xiaoliang Xu, Hui Liu, Ran Wu, Weiwen Zuo, Tiantao Wang, Dong Chen

2324 related Products with: Analysis of the correlation of the expression level of hypoxia-inducible factor-1α with the glycosylation of oral squamous cell carcinoma.

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#34304571   2021/07/25 To Up

-Linked--Acetylglucosaminylation of the RNA-Binding Protein EWS N-Terminal Low Complexity Region Reduces Phase Separation and Enhances Condensate Dynamics.

Many membraneless organelles are thought to be biomolecular condensates formed by phase separation of proteins and other biopolymers. Post-translational modifications (PTMs) can impact protein phase separation behavior, although for many PTMs this aspect of their function is unknown. -linked β-D--acetylglucosaminylation (-GlcNAcylation) is an abundant form of intracellular glycosylation whose roles in regulating biomolecular condensate assembly and dynamics have not been delineated. Using an approach, we found that -GlcNAcylation reduces the phase separation propensity of the EWS -terminal low complexity region (LCR) under different conditions, including in the presence of the arginine- and glycine-rich RNA-binding domains (RBD). -GlcNAcylation enhances fluorescence recovery after photobleaching (FRAP) within EWS LCR condensates and causes the droplets to exhibit more liquid-like relaxation following fusion. Following extended incubation times, EWS LCR+RBD condensates exhibit diminished FRAP, indicating a loss of fluidity, while condensates containing the -GlcNAcylated LCR do not. In HeLa cells, EWS is less -GlcNAcylated following knockdown, which correlates with its increased accumulation in a filter retardation assay. Relative to the human proteome, -GlcNAcylated proteins are enriched with regions that are predicted to phase separate, suggesting a general role of -GlcNAcylation in regulation of biomolecular condensates.
Michael L Nosella, Maria Tereshchenko, Iva Pritišanac, P Andrew Chong, Jeffrey A Toretsky, Hyun O Lee, Julie D Forman-Kay

1588 related Products with: -Linked--Acetylglucosaminylation of the RNA-Binding Protein EWS N-Terminal Low Complexity Region Reduces Phase Separation and Enhances Condensate Dynamics.

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#34298689   2021/07/12 To Up

RANBP2 Activates -GlcNAcylation through Inducing CEBPα-Dependent OGA Downregulation to Promote Hepatocellular Carcinoma Malignant Phenotypes.

-GlcNAcylation is an important post-translational modification (PTM) jointly controlled by -GlcNAc transferase (OGT) and -GlcNAcase (OGA). Aberrant hyper--GlcNAcylation is reported to yield hepatocellular carcinoma (HCC) malignancy, but the underlying mechanisms of the OGT/OGA imbalance responsible for HCC tumorigenesis remain largely unknown. Here, we report that RAN-binding protein 2 (RANBP2), one of the small ubiquitin-like modifier (SUMO) E3 ligases, contributed to malignant phenotypes in HCC. RANBP2 was found to facilitate CCAAT/enhancer-binding protein alpha (CEBPα) SUMOylation and degradation by direct interplay with CEBPα. As a transcriptional factor, CEBPα was verified to augment OGA transcription, and further experiments demonstrated that RANBP2 enhanced the -GlcNAc level by downregulating OGA transcription while not affecting OGT expression. Importantly, we provided in vitro and in vivo evidence of HCC malignant phenotypes that RANBP2 triggered through an imbalance of OGT/OGA and subsequent higher -GlcNAcylation events for oncogenic proteins such as peroxisome proliferative-activated receptor gamma coactivator 1 alpha (PGC1α) in a CEBPα-dependent manner. Altogether, our results show a novel molecular mechanism whereby RANBP2 regulates its function through CEBPα-dependent OGA downregulation to induce a global change in the hyper--GlcNAcylation of genes, such as PGC1α, encouraging the further study of promising implications for HCC therapy.
Xiaoming Liu, Xingyu Chen, Mengqing Xiao, Yuxing Zhu, Renjie Gong, Jianye Liu, Qinghai Zeng, Canxia Xu, Xiong Chen, Fen Wang, Ke Cao

2050 related Products with: RANBP2 Activates -GlcNAcylation through Inducing CEBPα-Dependent OGA Downregulation to Promote Hepatocellular Carcinoma Malignant Phenotypes.



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#34290742   2021/07/05 To Up

Identification of Causal Genes of COVID-19 Using the SMR Method.

Since the first report of COVID-19 in December 2019, more than 100 million people have been infected with SARS-CoV-2. Despite ongoing research, there is still limited knowledge about the genetic causes of COVID-19. To resolve this problem, we applied the SMR method to analyze the genes involved in COVID-19 pathogenesis by the integration of multiple omics data. Here, we assessed the SNPs associated with COVID-19 risk from the GWAS data of Spanish and Italian patients and lung eQTL data from the GTEx project. Then, GWAS and eQTL data were integrated by summary-data-based (SMR) methods using SNPs as instrumental variables (IVs). As a result, six protein-coding and five non-protein-coding genes regulated by nine SNPs were identified as significant risk factors for COVID-19. Functional analysis of these genes showed that UQCRH participates in cardiac muscle contraction, PPA2 is closely related to sudden cardiac failure (SCD), and OGT, as the interacting gene partner of PANO1, is associated with neurological disease. Observational studies show that myocardial damage, SCD, and neurological disease often occur in COVID-19 patients. Thus, our findings provide a potential molecular mechanism for understanding the complications of COVID-19.
Yan Zong, Xiaofei Li

1230 related Products with: Identification of Causal Genes of COVID-19 Using the SMR Method.

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#34288245   2021/07/20 To Up

Upregulation of OGT by Caveolin-1 promotes hepatocellular carcinoma cell migration and invasion.

Caveolin-1 (CAV1), a major structural protein of caveolae, is reported to exert a positive regulatory effect on tumor growth and to play a crucial role in hepatocellular carcinoma (HCC) cell metastasis by regulating glycosyltransferase expression and cellular glycosylation. However, the role of CAV1 in modulating protein glycosylation and tumor metastasis remains to be further elucidated. In the present study, we showed that CAV1 promoted the expression of O-GlcNAc transferase (OGT), which catalyzed the addition of O-GlcNAc residues to a variety of nuclear and cytoplasmic proteins. In human HCC cell lines with different metastatic potentials, high levels of OGT and cellular O-GlcNAcylation were associated with CAV1 expression and cell metastasis. Overexpression of CAV1 increased the levels of OGT and O-GlcNAcylation, and cell migration was also increased. Furthermore, CAV1 was found to reduce the expression of Runt-related transcription factor 2 (RUNX2) in HCC cells. Subsequently, this effect resulted in the attenuation of the RUNX2-induced transcription of microRNA24 (miR24), a microRNA previously shown to suppress OGT mRNA expression by targeting its 3' untranslated regions (UTR). Finally, we demonstrated that CAV1 induced cellular O-GlcNAcylation and HCC cell invasion. This study provides evidence of CAV1-mediated increases in OGT expression and O-GlcNAcylation. These data provide insight into a novel mechanism underlying HCC metastasis and suggest a novel strategy for the treatment of HCC.
Lingyan Wang, Yuan Feng, Cheng Zhang, Xixi Chen, Huang Huang, Wenli Li, Jianing Zhang, Yubo Liu

2359 related Products with: Upregulation of OGT by Caveolin-1 promotes hepatocellular carcinoma cell migration and invasion.

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