3.1.3 Non-Canonical JAK/STAT pathway
FIGURE 3 Non-canonical JAK-STAT signaling.
It’s widely aberrated that the effects of STATs are mediated by direct transcriptional induction of STAT genes. However, in Drosophila and some mammal cells a non-canonical JAK-STAT pathway was identified, which directly controls the heterochromatin stability. That indicates the JAK affects the gene expression without directly STAT transcriptional control but by controlling cellular epigenetic STATs(Hixson, Cogswell, Brooks-Kayal & Russek, 2019; Li, 2008). Here comes a new mode of JAK signaling: JAK over-activation globally disrupts heterochromatin; that would enable expression of genes not necessarily under direct STAT transcriptional regulation(Betz & Darnell, 2006).
Different from the canonical mode of JAK-STAT (inactivated STATs distribution in the cytoplasm), in the non-canonical mode of JAK-STAT signaling, unphosphorylated STAT is localized on heterochromatin which is associated with HP1 in the nucleus. JAKs or other tyrosine kinases increase STAT phosphorylation, that induces reducing in the amount of unphosphorylated STAT localized on heterochromatin, leads to HP1 displacement from heterochromatin and heterochromatin instability. On the one hand, dispersed phospho-STATs bind to cognitive sites in euchromatin to induce target-gene expression. On the other, genes originally localized in heterochromatin are now accessible to STAT or other transcription factors. Non-canonical JAK-STAT signaling regulates heterochromatin stability, resulting in altered histone H3 methylation and/or chromatin remodeling. The JAK/STAT over-activation disrupts heterochromatin [26]. Although, it has been demonstrated that perturbation of epigenetic gene regulation plays an important role in many human diseases like tumorigenesis. And there is still much that is unknown or poorly understood about the role of non-canonical JAK/STAT signaling in ARDS or other pulmonary diseases. There need more studies to reveal the JAK/STAT would cause how many kinds of disease in the human being.