Abstract
Background & Aims The c-Myc (Myc) bHLH-ZIP transcription factor is deregulated in most cancers. In association with Max, Myc controls target genes that supervise metabolism, ribosome biogenesis, translation and proliferation. This “Myc Network” cross-talks with the “Mlx Network”, which consists of the Myc-like proteins MondoA and ChREBP and Max-like Mlx. Together, this “Extended Myc Network” regulates both common and distinct genes targets. Here we studied the consequence of Myc and/or Mlx ablation in the liver, particularly those pertaining to hepatocyte proliferation, metabolism and spontaneous tumorigenesis.
Methods We examined the ability of hepatocytes lacking Mlx (MlxKO) or Myc+Mlx (double KO or DKO) to repopulate the liver over an extended period of time in a murine model of Type I tyrosinemia. We also compared this and other relevant behaviors, phenotypes and transcriptomes of the livers to those from previously characterized MycKO, ChrebpKO and MycKO x ChrebpKO mice.
Results Hepatocyte regenerative potential deteriorated as the Extended Myc Network was progressively dismantled. Genes and pathways dysregulated in MlxKO and DKO hepatocytes included those pertaining to translation, mitochondrial function and non-alcoholic fatty liver disease (NAFLD). The Myc and Mlx Networks were shown to cross-talk, with the latter playing a disproportionate role in target gene regulation. All cohorts also developed NAFLD and molecular evidence of early steatohepatitis. Finally, MlxKO and DKO mice displayed extensive hepatic adenomatosis.
Conclusions In addition to demonstrating cooperation between the Myc and Mlx Networks, this study revealed the latter to be more important in maintaining proliferative, metabolic and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis.
Synopsis The Myc and Mlx Networks exhibit extensive cross-talk and regulate distinct but overlapping sets of transcriptional targets. The current work demonstrates the cooperation between these two Networks in supporting the regenerative capabilities of normal hepatocytes while also revealing that the Mlx Network serves as a suppressor of spontaneous hepatic adenomatosis
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Grant Support: This work was supported by NIH RO1 grants DK103645 to A.W.D., CA174713 to E.V.P. and NCI grant R35 CA231989 to R.N.E and P.C. E.V.P. was also supported by a Mellon Foundation Grant and a UPMC CHP Research Advisory Committee Seed Award. A.R. and J.F. were supported by The UPMC CHP Summer Research Undergraduate Fellowship Program.
Disclosures: The authors declare no potential conflicts of interest.
Transcript Profiling: Gene Expres.sion Omnibus(GEO) (Accession number GSE181371(reviewer token: yvarsegmzpsdbun), GSE130178 and GSE114634).
result section updated with ENCODE chip-seq analysis. Figure 3 revised.
