Cycles of gene expression and genome response during mammalian tissue regeneration

Abstract

BackgroundCompensatory liver hyperplasia—or regeneration—induced by two-thirds partial hepatectomy (PH) permits the study of synchronized activation of mammalian gene expression, particularly in relation to cell proliferation. Here, we measured genomic transcriptional responses and mRNA accumulation changes after PH and sham surgeries.ResultsDuring the first 10–20 h, the PH- and sham-surgery responses were very similar, including parallel early activation of cell-division-cycle genes. After 20 h, however, whereas post-PH livers continued with a robust and coordinate cell-division-cycle gene-expression response before returning to the resting state by 1 week, sham-surgery livers returned directly to a resting gene-expression state. Localization of RNA polymerase II (Pol II), and trimethylated histone H3 lysine 4 (H3K4me3) and 36 (H3K36me3) on genes dormant in the resting liver and activated during the PH response revealed a general de novo promoter Pol II recruitment and H3K4me3 increase during the early 10–20 h phase followed by Pol II elongation and H3K36me3 accumulation in gene bodies during the later proliferation phase. H3K36me3, generally appearing at the first internal exon, was preceded 5′ by H3K36me2; 3′ of the first internal exon, in about half of genes H3K36me3 predominated and in the other half H3K36me2 and H3K36me3 co-existed. Further, we observed some unusual gene profiles with abundant Pol II but little evident H3K4me3 or H3K36me3 modification, indicating that these modifications are neither universal nor essential partners to Pol II transcription.ConclusionsPH and sham surgical procedures on mice reveal striking early post-operatory gene expression similarities followed by synchronized mRNA accumulation and epigenetic histone mark changes specific to PH.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0222-0) contains supplementary material, which is available to authorized users.

Toll-like receptor 5-mediated signaling enhances liver regeneration in mice

“…We next investigated the expression pattern of TLR5 in the liver of mice after PHx. A global transcriptome analysis of the mouse liver at various time points after PHx revealed significant up-regulation of TLR5 along with other TLRs (GSE95135) [ 24 ] (Fig. 1 b).…”

Genome-Wide Methylation Mapping Using Nanopore Sequencing Technology Identifies Novel Tumor Suppressor Genes in Hepatocellular Carcinoma

“…During liver regeneration, proproliferative genes are activated and antiproliferative genes are suppressed to allow quiescent hepatocytes to re-enter the cell cycle. Since aberrant liver regeneration initiates HCC formation [ 22 , 23 , 24 ], we examined the expression level of hypermethylated genes before and four hours after two-thirds partial hepatectomy (PH) in mouse to narrow down TSG candidates [ 25 ]. We focused on genes that were downregulated more than twofold, compared to control sham surgery (SH), with the added criterion that expression of these genes should have recovered one week post partial hepatectomy ( Figure 2 A).…”

“…To narrow down candidates for hypermethylated TSG, we integrated our methylation data with gene expression profiles from regenerated liver and primary HCCs (TCGA). Since transcriptome profiling data of human liver regeneration is not available at present, we analyzed gene expression profiling of hypermethylated genes during mouse liver regeneration using previously published RNA-Seq data [ 25 ], despite the fact that approximately one percent of human genes do not have a mouse orthologue and vice versa [ 56 ]. To our knowledge, we are the first to use this particular combined approach to identify tumor suppressor genes that can be functionally validated.…”

TSMiner: a novel framework for generating time-specific gene regulatory networks from time-series expression profiles

“…We downloaded an RNA-seq dataset associated with LR in mice following PH from the Gene Expression Omnibus (record: GSE95135) ( 9 ). Liver samples were collected at 12 time points post-PH along with a negative control group.…”

“…To evaluate the core functions of TSMiner, TF and pathway prediction, we downloaded an RNA-seq dataset associated with liver regeneration (LR) in mice following partial hepatectomy (PH) ( 9 ) and collected 113 TFs and 58 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in LR by text mining and manual curation. By applying TSMiner, DREM (v. 2.0) and four widely used clustering tools for LR RNA-seq data, we demonstrated the highest sensitivity and accuracy of TSMiner in detecting known LR-associated TFs and pathways.…”