Random assortment of genes within mammalian genomes establishes the potential for interference between neighboring genes with distinct transcriptional specificities. Long-range transcriptional controls further increase this potential. Exploring this problem is of fundamental importance to understanding gene regulation. In the human genome, the Igbeta (CD79b) gene is situated between the pituitary-specific human growth hormone (hGH) gene and its locus control region (hGH LCR). Igbeta protein is considered B-cell specific; its only known role is in B-cell receptor signaling. Unexpectedly, we found that hIgbeta is transcribed at high levels in the pituitary. This Igbeta transcription is dependent on pituitary-specific epigenetic modifications generated by the hGH LCR. In contrast, expression of Igbeta at its native site in B cells is independent of hGH LCR activity. These studies demonstrated that a gene with tissue-restricted transcriptional determinants (B cell) can be robustly activated in an unrelated tissue (pituitary) due to fortuitous positioning within an active chromatin domain. This 'bystander' gene activation pathway impacts on current concepts of tissue specificity and models of active chromatin domains.
Profibrotic regulatory mechanisms for tissue repair after traumatic injury have developed under strong evolutionary pressure to rapidly stanch blood loss and close open wounds. We have examined the roles played by two profibrotic mediators, transforming growth factor 1 (TGF1) and thrombin, in directing expression of the vascular smooth muscle ␣-actin (SM␣A) gene, an important determinant of myofibroblast differentiation and early protein marker for stromal cell response to tissue injury. TGF1 is a well known transcriptional activator of the SM␣A gene in myofibroblasts. In contrast, thrombin independently elevates SM␣A expression in human pulmonary myofibroblasts at the posttranscriptional level. A common feature of SM␣A up-regulation mediated by thrombin and TGF1 is the involvement of the cold shock domain protein YB-1, a potent repressor of SM␣A gene transcription in human fibroblasts that also binds mRNA and regulates translational efficiency. YB-1 dissociates from SM␣A enhancer DNA in the presence of TGF1 or its Smad 2, 3, and 4 coregulatory mediators. Thrombin does not effect SM␣A gene transcription but rather displaces YB-1 from SM␣A exon 3 coding sequences previously shown to be required for mRNA translational silencing. The release of YB-1 from promoter DNA coupled with its ability to bind RNA and shuttle between the nucleus and cytoplasm is suggestive of a regulatory loop for coordinating SM␣A gene output in human pulmonary myofibroblasts at both the transcriptional and translational levels. This loop may help restrict organ-destructive remodeling due to excessive myofibroblast differentiation. INTRODUCTIONFibrosis is a serious complication of chronic cardiopulmonary diseases and postsurgical complication of heart and lung transplant (Pickering and Boughner, 1990;Armstrong et al., 1997;Howell et al., 2002;Chapman, 2004). Although management of acute allograft rejection is accomplished through the use of immunosuppressive agents that can limit immune cell infiltration, the cause of chronic rejection and failure in accepted allografts is poorly understood thus offering no treatment solution short of retransplant. Leading the formation of scar tissue is a specialized stromal cell referred to as the myofibroblast that contains abundant microfilament networks composed of smooth muscle-specific contractile protein isoforms (Tomasek et al., 2002;Hinz and Gabbiani, 2003;Grotendorst et al., 2004). Chronic accumulation of myofibroblasts is associated with excessive extracellular matrix protein biosynthesis, hypercontractility, and organ-destructive remodeling. Vascular smooth muscle ␣-actin (SM␣A) is one of the major contractile proteins expressed by differentiated myofibroblasts (Darby et al., 1990;Ronnov-Jessen and Petersen, 1996;Hinz et al., 2001;Cogan et al., 2002). Normally, SM␣A-enriched myofibroblasts are early, transient participants in stromal wound healing processes. We reason that characterization of the initial molecular events associated with activation of the SM␣A gene in stromal cells would hel...
Zhao X, Chen YR, He G, Zhang A, Druhan LJ, Strauch AR, Zweier JL. Endothelial nitric oxide synthase (NOS3) knockout decreases NOS2 induction, limiting hyperoxygenation and conferring protection in the postischemic heart. Am J Physiol Heart Circ Physiol 292: H1541-H1550, 2007. First published November 17, 2006; doi:10.1152/ajpheart.00264.2006.-Although it has been shown that endothelial nitric oxide synthase (eNOS)-derived nitric oxide downregulates mitochondrial oxygen consumption during early reperfusion, its effects on inducible NOS (iNOS) induction and myocardial injury during late reperfusion are unknown. Wild-type (WT) and eNOS Ϫ/Ϫ mice were subjected to 30 min of coronary ligation followed by reperfusion. Expression of iNOS mRNA and protein levels and peroxynitrite production were lower in postischemic myocardium of eNOS Ϫ/Ϫ mice than levels in WT mice 48 h postreperfusion. Significantly improved hemodynamics (ϮdP/dt, left ventricular systolic pressure, mean arterial pressure), increased rate pressure product, and reduced myocardial infarct size (18 Ϯ 2.5% vs. 31 Ϯ 4.6%) were found 48 h after reperfusion in eNOS Ϫ/Ϫ mice compared with WT mice. Myocardial infarct size was also significantly decreased in WT mice treated with the specific iNOS inhibitor 1400W (20.5 Ϯ 3.4%) compared with WT mice treated with PBS (33.9 Ϯ 5.3%). A marked reperfusion-induced hyperoxygenation state was observed by electron paramagnetic resonance oximetry in postischemic myocardium, but PO 2 values were significantly lower from 1 to 72 h in eNOS Ϫ/Ϫ than in WT mice. Cytochrome c-oxidase activity and NADH dehydrogenase activity were significantly decreased in postischemic myocardium in WT and eNOS Ϫ/Ϫ mice compared with baseline control, respectively, and NADH dehydrogenase activity was significantly higher in eNOS Ϫ/Ϫ than in WT mice. Thus deficiency of eNOS exerted a sustained beneficial effect on postischemic myocardium 48 h after reperfusion with preserved mitochondrial function, which appears to be due to decreased iNOS induction and decreased iNOS-derived peroxynitrite in postischemic myocardium.oxygen; superoxide; peroxynitrite; mitochondria; electron paramagnetic resonance; ischemia-reperfusion NITRIC OXIDE (NO) is an important modulator of cardiac performance and left ventricular (LV) remodeling after myocardial infarction. In the setting of ischemic preconditioning, there is evidence that endothelial nitric oxide synthase (eNOS)-derived NO is important for the acute window of protection as well as the subsequent induction of inducible NOS (iNOS), triggering the delayed window of protection (4). However, there has been considerable controversy regarding the effect of eNOS-and eNOS-derived NO on myocardial ischemia-reperfusion injury. In eNOS knockout mice (eNOS Ϫ/Ϫ
RJ Jr, Strauch AR. Serum response factor neutralizes Pur␣-and Pur-mediated repression of the fetal vascular smooth muscle ␣-actin gene in stressed adult cardiomyocytes.
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