Dynamic remodeling of translation programs drives hepatocyte proliferation during liver regeneration
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE106140 | GEO | 2018/09/17
REPOSITORIES: GEO
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Project description:During liver regeneration, most new hepatocytes arise from pre-existing ones; yet, the underlying mechanisms that drive these cells from quiescence to proliferation remain poorly defined. By using high-resolution transcriptome profiling of purified hepatocytes isolated from quiescent and toxin-injured adult mouse livers,we uncover an overlap of regenerative response with developmental transcriptome programming. The translational remodeling modulates protein levels ofa set of splicing factors including Epithelial splicing regulatory protein 2 (ESRP2), which activates an early postnatal splicing program in regenerating hepatocytes. We find that regeneration-regulated exons are enriched within unstructured regions of proteins and frequently harbor amino-acid residues that can be post-translationally modified to influence protein-protein interactions.
2018-09-17 | GSE105944 | GEO
Project description:The recovery of liver mass is mainly mediated by proliferation and enlargement of hepatocytes after partial hepatectomy. Studying the gene expression profiles of hepatocytes after partial hepatectomy will be helpful in exploring the mechanism of liver regeneration. We used microarrays to further highlight the regulatory role of hepatocyte in liver regeneration at gene transcription level. Rat liver regeneration after partial hepatectomy (PH) is a good model to study the regulation of cell proliferation. We isolated hepatocytes from regenerating liver at 9 time points (2, 6, 12,24, 30, 36, 72, 120, and 168h) after PH and measured gene expression profiles of hepatocytes from 2h to 168h with rat Genome 230 2.0 gene chip. Each sample corresponding to one time point was hybridized onto one array. The experiment was repeated 3 times for each time point. In total, 10 time points were measured and 0h was used control group. After careful quality control analyses of each chip, Affymetrix GCOS 2.0 software was used to analyze the data. The relevance of gene expression profiles and biological processes was analyzed by bioinformatics and systems biology.
2014-02-28 | E-GEOD-55434 | biostudies-arrayexpress
Project description:Alternative splicing greatly expands the proteomic diversity but its functional impact is often unclear. Here, we identify a highly conserved and temporally coordinated cell-type-specific splicing program, which is activated in part by ESRP2 during postnatal liver development. Consistent with failure of many neonatal-to-adult splicing transitions, Esrp2 null mice exhibit persistent expression of fetal markers and loss of mature hepatocyte characteristics. Conversely, ectopic expression of ESRP2 in immature mouse or human hepatocytes results in a reciprocal switch in splicing. Our findings define an essential role for ESRP2 in generation of conserved repertoires of adult splice isoforms that facilitate postnatal liver maturation. Mouse liver RNA was isolated with Trizol (Invitrogen). Hi-Seq libraries were prepared and paired-end 100bp Illumina sequencing was performed on mouse liver samples from different developmental stages.
2015-11-04 | E-GEOD-67009 | biostudies-arrayexpress
Project description:Alternative splicing greatly expands the proteomic diversity but its functional impact is often unclear. Here, we identify a highly conserved and temporally coordinated cell-type-specific splicing program, which is activated in part by ESRP2 during postnatal liver development. Consistent with failure of many neonatal-to-adult splicing transitions, Esrp2 null mice exhibit persistent expression of fetal markers and loss of mature hepatocyte characteristics. Conversely, ectopic expression of ESRP2 in immature mouse or human hepatocytes results in a reciprocal switch in splicing. Our findings define an essential role for ESRP2 in generation of conserved repertoires of adult splice isoforms that facilitate postnatal liver maturation.
2015-11-04 | GSE67009 | GEO
Project description:The liver is the only organ in mammals, which fully regenerates after injury. To identify novel regulators of liver regeneration, we performed quantitative large-scale proteomics analysis of subcellular fractions from normal versus regenerating mouse liver. Proteins of the ubiquitin-proteasome pathway were rapidly regulated by partial hepatectomy, with the ubiquitin ligase Nedd4-1 being among the top hits. Knock-down of Nedd4-1 in hepatocytes in vivo through nanoparticle-mediated delivery of siRNA caused severe liver damage after partial hepatectomy and impaired regeneration, resulting in liver failure. Mechanistically, we demonstrate that Nedd4-1 is required for efficient activation of Erk1/2 signaling by receptor tyrosine kinases involved in liver regeneration through inhibition of receptor internalization, thus controlling a major pro-mitogenic and cytoprotective signaling pathway in the regenerating liver. These results highlight the power of large-scale proteomics to identify key players in liver regeneration and the importance of posttranslational regulation of growth factor signaling in this process.
2017-09-13 | PXD004108 | Pride
Project description:The recovery of liver mass is mainly mediated by proliferation and enlargement of hepatocytes after partial hepatectomy. Studying the gene expression profiles of hepatocytes after partial hepatectomy will be helpful in exploring the mechanism of liver regeneration. We used microarrays to further highlight the regulatory role of hepatocyte in liver regeneration at gene transcription level.
2014-02-28 | GSE55434 | GEO
Project description:The adult liver has exceptional ability to regenerate, but how it sustains normal metabolic activities during regeneration remains unclear. Here, we use partial hepatectomy (PHx) in tandem with single-cell transcriptomics to track cellular transitions and heterogeneities of ~22,000 liver cells through the initiation, progression, and termination phases of mouse liver regeneration. Our results reveal that following PHx, a subset of hepatocytes transiently reactivates an early-postnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Importantly, through combined analysis of gene regulatory networks and cell- cell interaction maps, we find that regenerating hepatocytes redeploy key developmental gene regulons, which are guided by extensive ligand–receptor mediated signaling events between hepatocytes and non-parenchymal cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular reprogramming that balances the metabolic and proliferation requirements of a regenerating liver.
2021-02-01 | GSE151309 | GEO
Project description:The liver has a remarkable capacity for regeneration after injury. Midlobular hepatocytes have been proposed as the most plastic hepatic cell type, providing definitive evidence that zone 2 of the liver lobule acts as a reservoir for hepatocyte proliferation during homeostasis and regeneration. However, the implication of other mechanisms beyond hyperplasia that contribute to liver repair have been little explored and the collaboration of another hepatocyte subpopulation has differed among previous studies depending on the model of liver injury used. Thus, re-examination of dynamics of hepatocytes during regeneration is critical to get a better understanding of underlaying mechanisms for potential cell therapy and treatment of liver diseases. Here, using a mouse model of hepatocyte- and non-hepatocyte-specific multicolor lineage tracing, we demonstrate that hepatocytes located in the midlobular region also undergo hypertrophy besides cell division in response to chemical, physical, and viral insults. Our study shows for first time that this subpopulation also combats liver impairment after infection with coronavirus. Furthermore, we demonstrate that pericentral hepatocyte subpopulation also expands in number and size during the repair process in collaboration with midlobular hepatocytes and Galectin-9-CD44 pathway may be critical for driving these processes. Interestingly, we identified transdifferentiation and cell fusion processes during liver regeneration after severe injury that may be key to recover hepatic function.
2024-01-12 | GSE250568 | GEO
Project description:The lipin phosphatidate phosphatase (PAP) enzymes (lipin 1, lipin 2, and lipin 3) catalyze a step in triglyceride and phospholipid biosynthesis, and genetic lipin deficiencies cause human disease that is triggered by metabolic stress, such as fasting. We assessed the protein interactome of lipins 1, 2, and 3 in hepatocytes, and identified unique protein associations between lipin 1 and U2 mRNA spliceosome components. Lpin1–/– mouse liver exhibited aberrant mRNA splicing in the fasted state, including mRNAs involved in mRNA processing and liver maturation. Aberrant splicing could be induced in cultured hepatocytes by lipin 1 knockdown or elevated phosphatidic acid levels, suggesting a role for lipin 1 PAP activity in splicing fidelity. Refeeding Lpin1–/– animals after fasting largely restored mRNA splicing fidelity. Reduced levels of ESRP2 splicing factor exclusively in the fasted state of Lpin1–/– liver was associated with widespread aberrant exon inclusion. These findings connect lipid homeostasis with mRNA splicing, and identify aberrant mRNA splicing in lipin 1 deficiency as a potential contributor to disease symptoms triggered by fasting.
2021-09-15 | GSE160984 | GEO
Project description:Tumor-specific alternative splicing is implicated in the progression of cancer, including clear cell renal cell carcinoma (ccRCC). Using ccRCC RNA-sequencing data from The Cancer Genome Atlas, we found that epithelial splicing regulatory protein 2 (ESRP2), one of the key regulators of alternative splicing in epithelial cells, is expressed in ccRCC. ESRP2 mRNA expression did not correlate with the overall survival rate of ccRCC patients, but the expression of some ESRP-target exons correlated with the good prognosis and with the expression of Arkadia (also known as RNF111) in ccRCC. Arkadia physically interacted with ESRP2, induced polyubiquitination, and modulated its splicing function. Arkadia and ESRP2 suppressed ccRCC tumor growth in a coordinated manner. Lower expression of Arkadia correlated with advanced tumor stages and poor outcomes in ccRCC patients. This study thus reveals a novel tumor-suppressive role of the Arkadia-ESRP2 axis in ccRCC. Expression of mRNA in a ccRCC cell line OS-RC-2 under the knockdown of Arkadia or ESRP2. Knock-down of ESRP2 was confirmed by RT-PCR because of low expression of ESRP2 which resulted in non-quantitative FPKM value.
2015-08-01 | E-GEOD-66741 | biostudies-arrayexpress