Cycles of gene expression and genome response during mammalian tissue regeneration

Abstract

Background: Compensatory 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. Results:During the first 10-20 hours, the PH-and sham-surgery responses were very similar, including parallel early activation of cell-division-cycle genes. After 20 hours, however, whereas post-PH livers continued with a robust and coordinate cell-division-cycle gene-expression response before returning to the resting state by one 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 hour 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.Conclusions: PH 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.

Differential regulation of RNA polymerase III genes during liver regeneration

“…We profiled H3K4me3, Pol II (RPB2 subunit), and Pol III (RPC4 subunit) occupancy in parallel at different time points after PH by chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq). The Pol II and H3K4me3 occupancy data have been used to study occupancy dynamics at Pol II genes (11). Here, we used the same data as well as the Pol III data to determine occupancy scores at Pol III genes, as described before (18) (Supplementary Table S1).…”

“…Expressed Pol III loci differ from silent ones by the nearby presence of histone marks such as H3K4me3 (2,6–8,10) typical of chromatin regions that are or have been actively transcribed by Pol II ((11) and references therein). Moreover, active Pol III loci tend to reside close to Pol II TSSs and to peaks of Pol II occupancy, which suggests that transcription of nearby Pol II and Pol III genes is somehow co-regulated (2,5–8,10).…”

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. Global transcriptome analysis of the mouse liver at various time points following PHx revealed a signi cant upregulation of TLR5 along with other TLRs (GSE95135) [29] (Fig. 1b).…”

Appendage regeneration in anamniotes utilizes genes active during larval‐metamorphic stages that have been lost or altered in amniotes: The case for studying lizard tail regeneration

“…The contemporaneous presence of genes for adaptive immunity, complex nervous circuits, or for other amniote functions somehow determines regeneration failure, as schematically indicated in Figure 5b,c. The analysis of the transcriptomes of healing skin and other mammalian organs (Brant et al, 2019;Li et al, 2001;Khaspur et al, 2013;Sass et al, 2017;Rib et al, 2018; Table 3) shows that inflammatory and immune genes have increased as number and types, starting from reptiles (Boehm, 2012;Zimmerman et al, 2008). It has been suggested that, like in anurans (Harty et al, 2003;Mescher et al, 2016;Tsujioka et al, 2015), the high immune competence reached in amniotes eliminates every "embryonic-like" type of antigen, including those formed after wounding so that a regenerative blastema cannot form (Alibardi, 2015(Alibardi, , 2017b(Alibardi, , 2019d.…”