“As Director of the Wake Forest University Translational Sciences Institute, I am dedicated to serving research and educating activities that will have a tangible effect on human health and disease. I am a physician scientist, with over 35 years of consistent NIH funding coupled to conducting laboratory research and mentoring trainees in translational research.”

Epigenetics and Severe Systemic Inflammation

Epigenetics, which describes genetic memory not primarily encoded in the human genome, is an emerging field with great importance in the phenotypes of many human diseases. Among these is inflammation. Our research team focuses on epigenetics and has determined that transcription processes, coupled to modifications in histones and methylation of DNA on CpG residues, generate epigenetic silencing of autotoxic proinflammatory genes that initiate the highly lethal process of severe systemic inflammation. Epigenetic events also control reprogramming of genes with sustained expression during severe systemic inflammation. Taken together, these processes contribute to the clinical phenotype associated with severe systemic inflammation. Our NIH funds are dedicated to identifying precise molecular events that control the epigenetic modification of chromatin to silence or sustain gene expression. A particularly important protein that is induced during severe systemic inflammation and that has dual function, which directs activating or repressing transcription by remodeling chromatin, is the NFkB factor, RelB. RelB orchestrates the assembly of histone methyltransferases (e.g. G9a),DNA methyltransferases (e.g., DNMT3a), and the adapter heterochromatin protein 1 (HP1). Our studies also seek to implicate inhibitory RNAs (RNAi) in gene reprogramming during inflammation. Our working model supports that severe systemic inflammation in humans is associated with formation of facultative heterochromatin, a physical state between transcriptionally responsive euchromatin and silent heterochromatin. This work is supported by RO-1 grants from the National Institutes of Health.

Recent Exemplary Publications

Chan C, Li L, McCall CE, Yoza B. Endotoxin Tolerance Disrupts Chromatin Remodeling and NF- B Transactivation at the IL-1 Promoter. J Immunol 175: 461-468, 2005.

Yoza, BK. Forest, L, McCall CE. Induction of RelB participates in endotoxin tolerance. J. Immunol. 2006. 177: 4080-4085.

McCall, CE, Yoza, B. Gene Silencing in Severe Systemic Inflammation. Am. J. Resp. Crit. Care. Med. 2007. 175: 763-767.

El Gazzar M, Yoza BK, Hu JY, Cousart SL, McCall, CE. Epigenetic silencing of TNF α during Endotoxin tolerance, J Biol Chem. 2007; 37:26857-26864.

PubMed link to CE McCall