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Identification of de novo STAT3 target gene in liver regeneration
Hui-Qi Zhang1, Sanae Haga, Moto Fukai
1Department of Innovative Surgery, National Research Institute for Child Health and Development, Tokyo, and Japan Association for the Advancement of Medical Equipment, Tokyo, Japan.
Unlabelled:
The process of liver regeneration is regulated by complex mechanisms. Although signal transducer and activator of transcription-3 (STAT3), a transcription factor which targets mainly mitotic genes, definitely plays an important role in liver regeneration, the exact roles of STAT3 are not completely understood.
Aim:
In this report, we tried to search for a new target of STAT3 involved in liver regeneration in mice.
Methods:
We generated liver-specific STAT3 knockout (L-S3KO) mice and a STAT3 knockout cell line of mouse origin. Using chromatin immunoprecipitation, we screened 12 genes to which STAT3 binds after partial hepatectomy (PH). Of these genes, we analyzed the S3-IE3 clone that is located on chromosome-3 and possesses STAT3 binding sites in it.
Results:
We showed that STAT3 binds to a specific site on S3-IE3, and that interleukin-6 (IL-6) stimulates its transcriptional activity. The mRNA and protein levels of the net gene, which is located downstream of S3-IE3, were negatively regulated in the control cells, but not in the STAT3 knockout cells after IL-6 stimulation. Similarly in in vivo mouse PH, the mRNA and protein levels of net were also negatively regulated after PH, but not in L-S3KO mice.
Conclusion:
The net gene is located downstream of a newly-recognized STAT3 binding site (S3-IE3) and negatively regulated after IL-6 stimulation and PH, although its role is still unclear.
Insights
Researchers identified a new STAT3 binding site (S3-IE3) involved in liver regeneration. This site regulates the net gene, which is negatively controlled by IL-6 and partial hepatectomy in mice.
Area of Science:
- Hepatology and molecular biology
- Gene regulation and transcription factors
Background:
- Liver regeneration is a complex process involving intricate regulatory mechanisms.
- Signal transducer and activator of transcription-3 (STAT3) is crucial for liver regeneration, primarily targeting mitotic genes, but its full role remains elusive.
Purpose of the Study:
- To identify novel STAT3 target genes implicated in mouse liver regeneration.
- To elucidate the specific binding sites and regulatory functions of STAT3 in this process.
Main Methods:
- Generation of liver-specific STAT3 knockout (L-S3KO) mice and a STAT3 knockout cell line.
- Chromatin immunoprecipitation (ChIP) to identify STAT3 binding sites after partial hepatectomy (PH).
- Analysis of the S3-IE3 clone on chromosome-3 for STAT3 binding and downstream gene regulation.
Main Results:
- STAT3 was confirmed to bind to the S3-IE3 site, with interleukin-6 (IL-6) enhancing its transcriptional activity.
- The downstream 'net' gene's mRNA and protein levels were negatively regulated by IL-6 in control cells but not in STAT3-deficient cells.
- In vivo studies showed similar negative regulation of 'net' gene expression after PH in control mice, but not in L-S3KO mice.
Conclusions:
- A novel STAT3 binding site, S3-IE3, was identified, which negatively regulates the 'net' gene.
- This regulation occurs downstream of IL-6 stimulation and during partial hepatectomy in mice.
- The precise function of the 'net' gene in liver regeneration requires further investigation.
