Dynamic remodeling of mRNA splicing and translation programs drives hepatocyte proliferation during liver regeneration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA415599 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6207420_1.fastq.gz | Fastqsanger.gz | |||
| SRR6207420_2.fastq.gz | Fastqsanger.gz | |||
| SRR6207421_1.fastq.gz | Fastqsanger.gz | |||
| SRR6207421_2.fastq.gz | Fastqsanger.gz | |||
| SRR6207416_1.fastq.gz | Fastqsanger.gz |
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Project description:Dynamic remodeling of translation programs drives hepatocyte proliferation during liver regeneration
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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 polysome fractions from purified hepatocytes isolated from quiescent and toxin-injured adult mouse livers,we uncover the mRNA transcripts regulated during liver regeneration. The translational remodeling modulates protein levels of a set of splicing factors including Epithelial splicing regulatory protein 2 (ESRP2), which activates an early postnatal splicing program in regenerating hepatocytes as well as metabolic genes.
2018-09-17 | GSE106140 | GEO
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:Liver regeneration is an extraordinarily complex process involving a variety of factors; however, the role of chromatin protein in hepatocyte proliferation is largely unknown. In this study, we investigated the functional role of high-mobility group box 2 (HMGB2), a chromatin protein in liver regeneration using wild-type and HMGB2-knockout (KO) mice. Liver tissues were sampled after 70% partial hepatectomy (PHx), and analyzed by immunohistochemistry using various markers of cell proliferation, including Ki-67, PCNA, cyclin D1, cyclin B1, EdU and pH3S10. In WT mice, hepatocyte proliferation was strongly correlated with the spatiotemporal expression of HMGB2; however, cell proliferation was significantly delayed in hepatocytes of HMGB2-KO mice. Quantitative PCR demonstrated that cyclin D1 and cyclin B1 mRNAs were significantly decreased in HMGB2-KO mice livers. Interestingly, hepatocyte size was significantly larger in HMGB2-KO mice at 36-72 h after PHx, and these results suggest that hepatocyte hypertrophy appeared in parallel with delayed cell proliferation. In vitro experiments demonstrated that cell proliferation was significantly decreased in HMGB2-KO cells. A significant delay in cell proliferation was also found in HMGB2-siRNA transfected cells. In summary, spatiotemporal expression of HMGB2 is important for regulation of hepatocyte proliferation and cell size during liver regeneration.
2022-04-03 | GSE199944 | GEO
Project description:MicroRNAs (miRNAs) constitute a new class of regulators of gene expression. Among other actions, miRNAs have been shown to control cell proliferation in development and cancer. However, whether miRNAs regulate hepatocyte proliferation during liver regeneration is unknown. We addressed this question by performing 2/3 partial hepatectomy (2/3 PH) on mice with hepatocyte-specific inactivation of DiGeorge syndrome critical region gene 8 (DGCR8), an essential component of the miRNA processing pathway. Hepatocytes of these mice were miRNA-deficient and exhibited a delay in cell cycle progression involving the G(1) to S phase transition. Examination of livers of wildtype mice after 2/3 PH revealed differential expression of a subset of miRNAs, notably an induction of miR-21 and repression of miR-378. We further discovered that miR-21 directly inhibits Btg2, a cell cycle inhibitor that prevents activation of forkhead box M1 (FoxM1), which is essential for DNA synthesis in hepatocytes after 2/3 PH. In addition, we found that miR-378 directly inhibits ornithine decarboxylase (Odc1), which is known to promote DNA synthesis in hepatocytes after 2/3 PH.Our results show that miRNAs are critical regulators of hepatocyte proliferation during liver regeneration. Because these miRNAs and target gene interactions are conserved, our findings may also be relevant to human liver regeneration.
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Project description:Supplemental NAD+ precursors show metabolic and functional benefits in rodent models of disease and are being explored as potential therapeutics in human studies. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down mechanisms of action. Here we provide evidence that for a well-established benefit of NAD+ precursors in mice, faster liver regeneration, nearly the entire effect can be attributed to the concentration of NAD+ in hepatocyte mitochondria. We find that mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1), as has previously been shown in cultured cells. Heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, while hepatocyte-specific overexpression is sufficient to enhance regeneration comparably to the effect of systemic supplements, despite increasing NAD+ only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.
2025-11-06 | PXD067549 | Pride
Project description:Oxidative phosphorylation (OXPHOS) is fundamental for life. OXPHOS complexes pose a unique challenge for the cell, because their subunits are encoded on two different genomes, the nuclear genome and the mitochondrial genome. Genomic approaches designed to study nuclear/cytosolic and bacterial gene expression have not been broadly applied to the mitochondrial system, thus the co-regulation of OXPHOS genes remains largely unexplored. Here we globally monitored mitochondrial and nuclear gene expression processes during mitochondrial biogenesis when OXPHOS complexes are synthesized. Nuclear- and mitochondrial- encoded OXPHOS transcript levels do not increase concordantly. Instead, we observe that mitochondrial and cytosolic translation are rapidly and dynamically regulated in a strikingly synchronous fashion. Furthermore, the coordinated translation programs are controlled unidirectionally through the intricate and dynamic control of cytosolic translation. Thus the nuclear genome carefully directs the coordination of mitochondrial and cytosolic translation to orchestrate the timely synthesis of each OXPHOS complex, representing an unappreciated regulatory layer shaping the mitochondrial proteome. Our whole-cell genomic profiling approach establishes a foundation for global gene regulatory studies of mitochondrial biology.
2016-05-11 | GSE74454 | GEO
Project description:Supplemental NAD+ precursors show metabolic and functional benefits in rodent models of disease and are being explored as potential therapeutics in human studies. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down mechanisms of action. Here we provide evidence that for a well-established benefit of NAD+ precursors in mice, faster liver regeneration, nearly the entire effect can be attributed to the concentration of NAD+ in hepatocyte mitochondria. We find that mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1), as has previously been shown in cultured cells. Heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, while hepatocyte-specific overexpression is sufficient to enhance regeneration comparably to the effect of systemic supplements, despite increasing NAD+ only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.
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Project description:Chromatin remodeling complexes instruct cellular differentiation and lineage specific transcription. The BRG1/BRM associated factor (BAF) complexes are important for several aspects of differentiation. We show that the catalytic subunit Brg1 has a specific role in cardiac precursors (CPs) to initiate cardiac gene expression programs and repress non-cardiac expression. Using immunoprecipitation immunopurification with mass spectrometry we determined the dynamic composition of BAF complexes during mammalian cardiac differentiation, identifying several cell-type specific subunits. We focused on the CP- and cardiomyocytes (CM)-enriched subunits BAF60c (SMARCD3) and BAF170 (SMARCC2). Baf60c and Baf170 co-regulate gene expression with Brg1 in CPs, and in CMs their loss results in broadly deregulated cardiac gene expression. BRG1, BAF60, and BAF170 modulate chromatin accessibility, to either promote accessibility at activated genes, while closing up chromatin at repressed genes. BAF60c and BAF170 are required for proper BAF complex composition, and BAF170 loss leads to retention of BRG1 at CP-specific enhancers. Thus, dynamic interdependent BAF complex subunit assembly modulates chromatin states and thereby participates in directing temporal gene expression programs in cardiogenesis.
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Project description:Bromodomain and extraterminal (BET) proteins recruit key components of basic transcriptional machinery to promote gene expression. Aberrant expression and mutations in BET genes have been identified in many malignancies. Small molecule inhibitors of BET proteins such as JQ1 have shown efficacy in preclinical cancer models, including affecting growth of hepatocellular carcinoma. BET proteins also regulate cell proliferation in nontumor settings. We recently showed that BET proteins regulate cholangiocyte-driven liver regeneration. Here, we studied the role of BET proteins in hepatocyte-driven liver regeneration in partial hepatectomy (PHx) and acetaminophen-induced liver injury models in mice and zebrafish. JQ1 was injected 2 or 16 hours after PHx in mice to determine effect on hepatic injury, regeneration, and signaling. Mice treated with JQ1 after PHx displayed increased liver injury and a near-complete inhibition of hepatocyte proliferation. Levels of Ccnd1 mRNA and Cyclin D1 protein were reduced in animals injected with JQ1 16 hours after PHx and were even further reduced in animals injected with JQ1 2 hours after PHx. JQ1-treated zebrafish larvae after acetaminophen-induced injury also displayed notably impaired hepatocyte proliferation. In both models, Wnt signaling was prominently suppressed by JQ1. Our results show that BET proteins regulate hepatocyte proliferation-driven liver regeneration, and Wnt signaling is particularly sensitive to BET protein inhibition.
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