Xenobiotic-responsive hepatic long non-coding RNAs

异生素反应性肝脏长非编码RNA

• 批准号: 10809269
• 负责人: DAVID J WAXMAN
• 金额: $ 7.78万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809269
• 关键词: Abbreviations; Address; Adult; Affect; Agonist; Architecture; Automobile Driving; Benzene; Biological; CRISPR interference; Cells; Chemical Exposure; Chemicals; Chromatin; Chromatin Loop; Cirrhosis; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Complex; Deoxyribonucleases; Dependovirus; Development; Diagnosis; Diet; Disease; Disease Progression; Environment; Environmental Pollutants; Enzymes; Epigenetic Process; Etiology; Evaluation; Event; Exposure to; Fatty Liver; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Genome; Genomics; Guide RNA; Health; Hepatic; Hepatic lobule; Hepatocyte; High Fat Diet; Human; Industrialization; Inflammation; Knock-out; Ligands; Link; Liver; Liver Cirrhosis; Liver Failure; Liver diseases; Lobule; Mediator; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Mus; Nuclear; Nuclear Pore Complex; Nuclear Receptors; Orthologous Gene; PPAR alpha; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Physiological Processes; Positioning Attribute; Primary carcinoma of the liver cells; Process; Proteins; Receptor Activation; Regulator Genes; Research; Role; Serotyping; Site; Specificity; Testing; Time; Tissues; Untranslated RNA; Work; Xenobiotic Metabolism; Xenobiotics; advanced disease; blood glucose regulation; carbohydrate metabolism; cell type; constitutive androstane receptor; endonuclease; environmental chemical; environmental chemical exposure; fatty liver disease; gene network; gene regulatory network; gene repression; in vivo; insight; interest; lipid biosynthesis; lipid metabolism; liver development; liver metabolism; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel marker; pregnane X receptor; prevent; programs; promoter; prototype; receptor; single nucleus RNA-sequencing; therapeutic target; transcription factor; transcription termination; transcriptome; transcriptomic profiling

7. Project Summary/Abstract Many industrial chemicals, environmental pollutants and other xenochemicals activate transcription factors belonging to the nuclear receptor superfamily, which leads to widespread genomic, epigenetic and transcriptional changes that disrupt key biological pathways and metabolic processes in liver and other tissues. The studies proposed focus on the liver nuclear receptor CAR (Constitutive Androstane Receptor; NR1I3), which is activated by structurally diverse xenochemicals and regulates transcription of hundreds of protein-coding genes important for processes such as xenobiotic metabolism, lipogenesis, glucose homeostasis, and inflammation, and has been implicated as a regulator of non-alcoholic fatty liver disease (NAFLD) development. We have discovered that xenobiotic agonists of CAR and other xenobiotic-responsive receptors induce or repress the transcription of several hundred nuclear-enriched long non-coding RNAs (lncRNAs) with epigenetic and gene regulatory potential, many of which have human orthologs. This proposal builds on these findings and on recent advances in liver cell zonation, single cell-based transcriptomic profiling, and gene co-expression network analysis to elucidate in an intact mouse liver model the effects of CAR-responsive lncRNAs on fatty liver disease induced by foreign chemical exposure. The studies proposed test the hypothesis that a subset of CAR-responsive lncRNAs control hepatic gene regulatory networks driving NAFLD and downstream pathologies, dysregulating processes such as lipid and carbohydrate metabolism, hepatic architecture and mitochondrial function in a liver cell type-specific and hepatic lobule zone-dependent manner. The work proposed uses TCPOBOP (1,4-bis[2-(3,5-dichloro-pyridyloxy)]benzene), a prototypic non- genotoxic chemical and CAR-specific agonist ligand, to address the seemingly paradoxical finding that persistent exposure to foreign chemical CAR activators induces NAFLD in mice fed normal chow diet, but suppresses NAFLD development in mice fed a high fat diet. These studies will elucidate the role of CAR, and the lncRNAs that it regulates, in fatty liver disease etiology and progression. Results obtained will give critical insight into the underlying mechanisms by which foreign chemicals dysregulate CAR-dependent metabolic pathways linked to NAFLD, which affects 25% of US adults and is a major cause of cirrhosis, hepatocellular cancer and liver failure. This work will refocus research efforts on xenochemical action to include mechanistic studies of single cell-based, spatially zonated gene regulatory networks and the non-coding transcriptome, and will serve as a paradigm for other foreign chemical-activated receptors that dysregulate gene expression in complex ways. Together, the proposed studies on CAR-responsive lncRNAs and their role in xenochemical- induced liver pathology may lead to new ways to prevent, diagnose or treat liver diseases induced by chemical exposure.

7. 项目总结/文摘

项目成果

Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome.

• DOI: 10.1371/journal.pone.0150284
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Oshida K;Waxman DJ;Corton JC
• 通讯作者: Corton JC

Impact of Neonatal Activation of Nuclear Receptor CAR (Nr1i3) on Cyp2 Gene Expression in Adult Mouse Liver.

新生儿核受体 CAR (Nr1i3) 激活对成年小鼠肝脏 Cyp2 基因表达的影响。

• DOI: 10.1093/toxsci/kfac032
• 发表时间: 2022
• 期刊: Toxicological sciences : an official journal of the Society of Toxicology
• 作者: Shin,Aram;Waxman,DavidJ
• 通讯作者: Waxman,DavidJ

Long non-coding RNA G23Rik attenuates fasting-induced lipid accumulation in mouse liver.

• DOI: 10.1016/j.mce.2022.111722
• 发表时间: 2022-11-01
• 期刊: MOLECULAR AND CELLULAR ENDOCRINOLOGY
• 影响因子: 4.1
• 作者: Kim, Donghwan;Kim, Bora;Brocker, Chad N.;Karri, Kritika;Waxman, David J.;Gonzalez, Frank J.
• 通讯作者: Gonzalez, Frank J.

Global analysis of expression, maturation and subcellular localization of mouse liver transcriptome identifies novel sex-biased and TCPOBOP-responsive long non-coding RNAs.

• DOI: 10.1186/s12864-021-07478-5
• 发表时间: 2021-03-24
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Goldfarb CN;Waxman DJ
• 通讯作者: Waxman DJ

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting.

• DOI: 10.1038/s41467-020-19554-7
• 发表时间: 2020-11-17
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Brocker CN;Kim D;Melia T;Karri K;Velenosi TJ;Takahashi S;Aibara D;Bonzo JA;Levi M;Waxman DJ;Gonzalez FJ
• 通讯作者: Gonzalez FJ