Co-option of the PRDM14-CBFA2T complex from motor neurons to pluripotent cells during vertebrate evolution.

Gene regulatory networks underlying cellular pluripotency are controlled by a core circuitry of transcription factors in mammals, including POU5F1. However, the evolutionary origin and transformation of pluripotency-related transcriptional networks have not been elucidated in deuterostomes. PR domain-containing protein 14 (PRDM14) is specifically expressed in pluripotent cells and germ cells, and is required for establishing embryonic stem cells (ESCs) and primordial germ cells in mice. Here, we compared the functions and expression patterns of PRDM14 orthologues within deuterostomes. Amphioxus PRDM14 and zebrafish PRDM14, but not sea urchin PRDM14, compensated for mouse PRDM14 function in maintaining mouse ESC pluripotency. Interestingly, sea urchin PRDM14 together with sea urchin CBFA2T, an essential partner of PRDM14 in mouse ESCs, complemented the self-renewal defect in mouse Prdm14 KO ESCs. Contrary to the Prdm14 expression pattern in mouse embryos, Prdm14 was expressed in motor neurons of amphioxus embryos, as observed in zebrafish embryos. Thus, Prdm14 expression in motor neurons was conserved in non-tetrapod deuterostomes and the co-option of the PRDM14-CBFA2T complex from motor neurons into pluripotent cells may have maintained the transcriptional network for pluripotency during vertebrate evolution.This article has an associated 'The people behind the papers' interview.

Cotreatment with interferon-alpha and -gamma reduces liver fibrosis in a rat model.

Background/Aims: Interferon-alpha is used widely to treat viral hepatitis. Interferon-gamma modulates a system attacking infected cells and also has an anti-fibrotic effect. A treatment with interferon-alpha and -gamma has undergone trials in eliminating hepatitis C virus. We investigated effects of cotreatment in a liver fibrosis model to explore anti-fibrotic effects. Methods: Rats were assigned to groups including normal controls (NC), CCl(4) controls, rat interferon-alpha treatment, rat interferon-gamma treatment, and cotreatment. All groups except normal controls received CCl(4) orally for 8 weeks. At the beginning of the third week of exposure, 6 weeks of treatment were initiated according to interferon group. Digitally analyzed immunohistochemistry, biochemical assays, and Northern analysis were performed. Results: Pixels (x10(5)) per field containing immunoreactive type III collagen (fibrotic density) in CCl(4) controls, interferon-alpha, interferon-gamma, and cotreatment groups respectively were [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text]. Liver hydroxyproline content correlated with fibrotic density, and was significantly low in the cotreatment group. Plasma hyaluronate and transaminase were significantly low in cotreatment and interferon-alpha groups. Northern blotting showed lowest mRNA expression for type I collagen, desmin, transforming growth factor (TGF)-beta1, and matrix metalloproteinase-2 mRNA in the cotreatment group; tissue inhibitor of metalloproteinase-1 and -2 mRNAs were significantly low in the interferon-gamma group. Conclusions: Cotreatment can suppress collagen and transforming growth factor-beta1 and has an overall anti-fibrotic effect without exacerbating inflammation.

Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice.

The equilibrium between the production and degradation of collagen is rigorously controlled by a number of growth factors and cytokines. Interferon alfa (IFN-alpha) is now widely used for the treatment of chronic hepatitis C, which can improve serum levels of fibrotic markers and the degree of hepatic fibrosis, not only in patients who responded to therapy but also in those in whom it is ineffective. These findings may suggest that IFN-alpha possesses direct antifibrotic effects in addition to its antiviral activity. However, in contrast to IFN-gamma, which has been shown to suppress collagen gene transcription, little is known about the mechanisms responsible for the antifibrotic effects of IFN-alpha. Here, we report that IFN-alpha, when administered into transgenic mice harboring the alpha2(I) collagen gene (COL1A2) promoter sequence, significantly repressed promoter activation and prevented the progression of hepatic fibrosis induced by carbon tetrachloride injection. Transient transfection assays indicated that IFN-alpha decreased the steady-state levels of COL1A2 messenger RNA (mRNA) and inhibited basal and TGF-beta/Smad3-stimulated COL1A2 transcription in activated hepatic stellate cells (HSC). These inhibitory effects of IFN-alpha on COL1A2 transcription were exerted through the interaction between phosphorylated Stat1 and p300. Blocking of the IFN-alpha signal by overexpressing the intracellular domain-deleted IFN receptor increased basal COL1A2 transcription and abolished the inhibitory effects of IFN-alpha. In conclusion, our results indicate that IFN-alpha antagonizes the TGF-beta/Smad3-stimulated COL1A2 transcription in vitro and suppresses COL1A2 promoter activation in vivo, providing a molecular basis for antifibrotic effects of IFN-alpha.