Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of livers at different time points after partial hepatectomy and at different time points post conception to elucidate gene expression similarities between regenerating and developing liver.

ABSTRACT: Normal adult liver is uniquely capable of renewal; and repair after injury. Whether this response; represents simple hyperplasia of various liver elements; or requires recapitulation of the genetic program of; the developing liver is not known. To study these possibilities, we examined transcriptional programs of adult liver after partial hepatectomy and contrasted these with developing embryonic liver. Principal component analysis demonstrated that the time series of gene expression during liver regeneration does not segregate according to developmental transcription patterns. Gene ontology analysis revealed that liver restoration after hepatectomy and liver development differ dramatically with regard to transcription factors and chromatin structure modification. In contrast, the tissues are similar with regard to proliferationassociated genes. Consistent with these findings, realtime polymerase chain reaction showed transcription factors known to be important in liver development are not induced during liver regeneration. These three lines of evidence suggest that at a transcriptional level, restoration of liver mass after injury is best described as hepatocyte hyperplasia and not true regeneration. We speculate this novel pattern of gene expression may underlie the unique capacity of the liver to repair itself after injury. Experiment Overall Design: In order to elucidate the molecular similarities between regenerating and developing liver, we performed high-density microarray analysis using Affymetrix MG 430 2.0 chips for targets at 0, 1, 2, 6, 12, 18, 24, 30, 48, and 72 hours after partial hepatectomy and at 10.5, 11.5, 12.5, 13.5, 14.5, and 16.5 days post conception (dpc). Experiment Overall Design: Each experimental time point is represented by two separate samples, each consisting of at least 3 pooled tissues from different animals. For example, 6 hepatectomies were performed for the 1 hour post-hepatectomy time point. Time 0 is used as control.

ORGANISM(S): Mus musculus

SUBMITTER: Hasan Huseyin Otu

PROVIDER: E-GEOD-6998 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Restoration of liver mass after injury requires proliferative and not embryonic transcriptional patterns.

Otu Hasan H HH Naxerova Kamila K Ho Karen K Can Handan H Nesbitt Nicole N Libermann Towia A TA Karp Seth J SJ

The Journal of biological chemistry 20070116 15

Normal adult liver is uniquely capable of renewal and repair after injury. Whether this response represents simple hyperplasia of various liver elements or requires recapitulation of the genetic program of the developing liver is not known. To study these possibilities, we examined transcriptional programs of adult liver after partial hepatectomy and contrasted these with developing embryonic liver. Principal component analysis demonstrated that the time series of gene expression during liver re ...[more]

PMID: 17227769

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Project description:Understanding congenital liver disease requires elucidation of the signaling pathways and transcriptional events in the developing liver. Comprehensive assessment of gene expression between 10.5 and 16.5 dpc in the developing mouse liver and comparison with adult liver and non-hepatic embryonic tissue was validated with real-time PCR and in situ hybridization. The broad nature of the analysis provides insights into patterns of genetic control of hepatogenesis. Pathways implicated in human disease are highly regulated at the transcriptional level. Rather than activating or inhibiting a pathway or biological process by altering the expression of a single signaling molecule, transcriptional changes in large numbers of genes in a pathway or process are regulated in a coordinated manner. For example, both TGF-beta and Notch signaling is inhibited during hepatogenesis not just by decreasing transcription of multiple pathway members, but also with a complementary increase in the transcription of a pathway inhibitor. Similarly, genes related to specific biological processes exhibit strong temporal synchronization in which multiple members of the pathway have similar transcriptional regulation over time. Global coordination of signaling or functional families at the transcriptional level may be a mechanism to produce robustness of the desired outcomes. In addition, this comprehensive analysis provides a database for the further study of transcriptional events during liver development by identifying liver-specific, highly regulated genes. Experiment Overall Design: In order to provide transcriptional profile of the developing liver compared both to normal adult liver and non-hepatic embryonic tissueswe performed high-density microarray analysis using Affymetrix MG 430 2.0 chips for embryonic liver samples at 10.5, 11.5, 12.5, 13.5, 14.5, and 16.5 days post conception (dpc), embryo-minus liver tissues at 10.5, 11.5, 12.5, and 14.5 dpc, and normal 10-week-old adult mouse liver. Each sample consisted of at least five embryos.

Project description:Liver is uniquely capable to repair itself after injury. Multiple molecular and biochemical processes initiated after partial hepatectomy, lead to proliferation of all cells within the liver. MicroRNAs (miRNAs) are a class of highly abundant non-coding RNA molecules that cause post-transcriptional gene repression and are involved in several biological processes including cell cycle regulation and differentiation. We examined the expression levels of miRNAs in liver tissue received from control mice (L0) and compared them with the corresponding levels in liver tissue 12 hours after liver regeneration induced by 2/3 partial hepatectomy (L12). MicroRNA expression was investigated using microRNA profiling. Further qPCR analysis was used for validation of the differentially expressed microRNAs at an early stage of liver regeneration, induced by 2/3 partial hepatectomy. TargetScan and Gene Ontology (GO) analysis was performed in order to identify the possible miRNA target genes and their ontology, respectively. A subset of miRNAs were found to be differentially expressed during liver regeneration. Mmu-miR-21 and mmu-miR-30b* showed the higher levels of up-regulation in liver tissue from the hepatectomized mice at the end of the experiment (L12) compared to the sham operated mice (L0). Mmu-miR-21 up-regulation was further confirmed by qPCR. In situ hybridization (ISH) revealed that mmu-miR-21 exhibited the higher levels of expression at 12 hours post hepatectomy. On the contrary, mmu-miR-34c*, mmu-miR-144, mmu-miR-207, mmu-miR-207, mmu-miR-451, mmu-miR-582-3p and mmu-miR-290-5p exhibited <0.5 down-regulation in liver tissue after partial hepatectomy in L12 vs. L0 mice. Microarrays and qPCR results were in good agreement (Pearson correlation = 0.881). Our results provide important information regarding how microRNAs are deferentially expressed in murine liver tissue before and after partial hepatectomy. The early up-regulation of mmu-miR-21 during the process of liver regeneration suggests a regulatory role in liver regeneration in vivo. Twenty male wild type mice C57BL6J (8 weeks old) fed a standard diet were used for the liver regeneration experiment. Mice were housed in the animal facility of the University of Patras Medical School in temperature-, light- and humidity-controlled rooms with a 12-h light/dark cycle. All animal procedures were approved by the institutional review board of the University of Patras Medical School and were in accordance with EC Directive 86/609/EEC. A 2/3 partial hepatectomy (PH) was performed on 10 mice according to a recently published standardized protocol whereby the median and left lobes of the liver were removed and another 10 sham operated mice were used as the control group. The liver was allowed to regenerate and mice were sacrificed 12 hours after operation. Liver samples were collected from the sham operated mice (L0) and the hepatectomized mice at the end of the experiment (L12).

Dataset Information

Transcription profiling of livers at different time points after partial hepatectomy and at different time points post conception to elucidate gene expression similarities between regenerating and developing liver.

Publications

Restoration of liver mass after injury requires proliferative and not embryonic transcriptional patterns.

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