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Research Interests:
The mechanisms of epigenetic reprogramming and transcriptional regulation that regulate acute inflammatory gene expression in severe systemic inflammation.
Current Research:
Epigenetic gene reprogramming is an emerging concept relevant to human diseases. The general objective of my research is to investigate epigenetics of severe systemic inflammation (SSI). SSI blood and tissue leukocytes show gene‐specific reprogramming with repressed transcription of acute proinflammatory genes like TNFα and IL‐1β and activated transcription of other gene sets like IκBα, antimicrobial peptides, and anti‐inflammatory cytokines. Clinical improvement follows reversal of SSI gene reprogramming. I reported TNFα transcription repression and a ‘histone code’ shift to histone H3 lysine9 di‐methylation (H3K9me2), H3 serine 10 dephosphorylation(H3S10), and repressor heterochromatin protein 1 (HP1) promoter binding in an SSI cell model. These results support that epigenetic mechanisms participate in repressing acute inflammatory genes and sustaining often lethal immunosuppression observed in SSI patients. I hypothesize that SSI is accompanied by acute proinflammatory chromatin changes from euchromatin characteristics (expressed) to that of heterochromatin (repressed).
Preliminary data in an SSI cell model identify candidate nucleosome‐modifying proteins at the TNFα promoter with binding of G9a and SUV39h1 methyl transferases, LSD1 demethylase, and heterochromatin adapter protein 1 (HP1) in the transcriptionally repressed state. Conversely, association of MSK1 and Aurora B histone H3 kinases in the transcriptionally activated state suggests a reciprocal relationship beween methylated and phosphorylated H3. Preliminary data also support DNA CpG hypermethylation of the TNFα promoter in the repressed transcription state with concomitant binding of DNA methyltransferases Dnmt3a and 3b and adapter proteins MeCP2 and MBD1. I am investigating the epigenetic paradigm in SSI using a cell model and human blood leukocytes obtained from patients with SSI. Techniques utilize genetic (transfection of expression plasmids and/or siRNA) and biochemical (chromatin immunoprecipitation, DNA sequence, DNAase footprint, immunoblot, and mRNA quantitation) analyses.
Recent Publications:
El Gazzar M, Yoza BK, Hu JY, Cousart SL, McCall CE. Epigenetic silencing of tumor necrosis factor alpha during endotoxin tolerance. J Biol Chem. 2007 Sep 14;282(37):26857-64.
El Mezayen R, El Gazzar M, Seeds MC, McCall CE, Dreskin SC, Nicolls MR. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett. 2007 Jul 31;111(1):36-44.
El Gazzar MA, El Mezayen R, Nicolls MR, Dreskin SC. Thymoquinone attenuates proinflammatory responses in lipopolysaccharide-activated mast cells by modulating NF-kappaB nuclear transactivation. Biochim Biophys Acta. 2007 Apr;1770(4):556-64.
El Gazzar M, El Mezayen R, Nicolls MR, Marecki JC, Dreskin SC. Downregulation of leukotriene biosynthesis by thymoquinone attenuates airway inflammation in a mouse model of allergic asthma. Biochim Biophys Acta. 2006 Jul;1760(7):1088-95.
El Mezayen R, El-Gazzar M, Nicolls M, Marecki J, Dreskin SC, Nomiyama H. Effect of thymoquinone on cyclooxygenase expression and prostaglandin production in a mouse model of allergic lung inflammation. Immunol Lett. 2006 July 15;106(1):72-81.
For a listing of additional publications, refer to PubMed, a service provided by the National Library of Medicine
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