As a co factor CIITA lacks
As a co-factor, CIITA lacks the ability to recognize and directly bind to specific DNA elements to regulate transcription; instead, it relies on interaction with sequence-specific transcription factors (TFs) to be recruited to the chromatin. Therefore, the observation that CIITA binds to a specific region of the eNOS promoter (−430/−168) compels the question as to whether there exit within this region of the eNOS promoter conserved binding motifs for transcriptional repressors that may potentially recruit CIITA. A previous report by Neumann et al demonstrates that Sp3, via binding to the −379/−358 region of the eNOS promoter, mediates TNF-α induced repression of eNOS transcription . It is tempting to speculate that an interaction between Sp3 and CIITA may be responsible for SUV39H1 recruitment and therefore IFN-γ induced eNOS trans-repression. Alternatively, it is well established that CIITA forms a multi-protein enhanceosome to activate MHC II transcription. It is possible that several sequence-specific TFs, Sp3 included, cooperatively recruit CIITA to the proximal eNOS promoter to repress transcription. Further delineation of the CIITA interactome in endothelial r407 will hopefully shed additional light on this unsolved question.
Our understanding with regard to the role of SUV39H1 in the pathogenesis of cardiovascular diseases is limited. Previously we have reported that SUV39H1 deficiency or pharmaceutical inhibition protects the mice from ischemic heart disease (IHD) likely by curbing ROS generation in cardiomyocytes in a SIRT1-dependent manner [20,48]. Intriguingly, there is abundant evidence to support a cardioprotective role for eNOS. For instance, eNOS expression is down-regulated in ischemic hearts in mice . eNOS over-expression protects whereas eNOS deficiency exacerbates IHD in mice [50,51]. These observations, combined with our new findings summarized here, appear to argue for SUV39H1-mediated eNOS repression in endothelial cells as a potential mechanism underlying IHD. Future studies using an endothelial-specific SUV39H1 knockout mouse line would help clarify this issue.
Although we demonstrate that SUV39H1 may regulate eNOS trans-repression by influencing H3K9 trimethylation surrounding its promoter, we suspect this scenario encapsulates the full mechanism whereby SUV39H1 contributes to IFN-γ induced eNOS repression. Our data suggest that SUV39H1 over-expression enhances (Fig. 5E) while SUV39H1 knockdown (Fig. 6F) attenuates the repression of the eNOS promoter in reporter assay thus raising the possibility that SUV39H1 may directly methylate a non-histone transcription factor (e.g., CIITA) to modulate transcription. CIITA activity is known to be susceptible to multiple forms of post-translational modifications . We have previously shown that interaction with the methyltransferase PRMT1 alters arginine methylation of CIITA and suppresses its transcriptional activity in macrophages; it is unclear whether CIITA could be lysine-methylated . On the other hand, there have been only scattered reports on non-histone substrates for SUV39H1 [54,55]. It would be of great interest to determine whether SUV39H1 could, in addition to influencing locus-specific histone methylation, directly modulate the methylation status of CIITA (or other transcription factors) to promote endothelial dysfunction.
In summary, our data unveil a previously unknown function for CIITA in vascular endothelial cells. Small-molecule inhibitors of SUV39H1 have been discovered or developed although their specificities are questionable . Screening for compounds that selectively inhibit SUV39H1 activity may yield novel interventional strategies for vascular endothelial disorders.
Introduction Physiological systems operate in finely coordinated manner to ensure the optimal oxygenation of cells in each organism. Inadequate or limited supply of oxygen from blood stream to the cells results in hypoxia. This phenomenon of hypoxia is a major predisposing factor for several pathological conditions like malignant tumors, myocardial and cerebral ischemia, hypertension, heart infarction, stroke and obstructive sleep apnea (OSA) [1,2]. Increase in altitude is associated with fall in partial pressure of oxygen and thus lower inspired oxygen resulting in hypobaric hypoxia. This condition is often encountered by high altitude sojourners like mountaineers, skiers, miners and pilgrims and results in several life threatening conditions. All organisms are able to trigger an adaptive response to cope with the deleterious effects of hypoxia. The acute exposure elicits activation of pre-existing proteins while the chronic exposure activates gene transcription and several post-transcriptional modifications [1,3].