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Investigation of the molecular mechanism of liver regeneration by the multi-omics approach

ABSTRACT: Liver regeneration has fascinated the field of regenerative medicine due to its outstanding capacity to undergo a substantial regeneration. The capacity to regenerate is likely to be encoded as a plasticity of molecular networks within the liver. While several reports have utilized massive molecular profiling approaches, a bird-like view of the molecular processes is still lacking. Here, by applying a combination of comprehensive analysis of epigenome, transcriptome and proteome, we depict the molecular landscape of liver regeneration. We demonstrate that histone H3K4 was tri-methylated at promoter regions of many loci, among which only a fraction including cell cycle related genes were transcriptionally up-regulated. Cistrome analysis guided by the histone methylation patterns and transcriptome identified FOXM1 as the key transcription factor to promote liver regeneration, which was confirmed using hepatocytes in vitro. Conditional protein degradation was also observed. These sets of informational resources will be useful to further investigate liver regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE73050 | GEO | 2017/09/07

SECONDARY ACCESSION(S): PRJNA295999

REPOSITORIES: GEO

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Project description: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.

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Investigation of the molecular mechanism of liver regeneration by the multi-omics approach

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