Associate Professor, BCMB
Ph.D. Physical Chemistry, Loyola University, Chicago IL
The finely tuned control of gene expression is central to all biological processes. Numerous studies have demonstrated the existence of multiple layers of transcriptional activity. My lab explores alternative mechanisms that control the specificity of gene transcription with biophysical measurements and genome-scale studies. The goal is to model the functional mechanism of the nuclear receptor family of transcription factors.
Nuclear receptors (NR) are intracellular receptors whose activity is controlled by specific extracellular stimuli such as lipophilic small-molecule hormones. These hormone-regulated NR proteins direct virtually every aspect of human physiology and improper function can lead to several disease states such as prostate and breast cancer, diabetes, obesity, heart disease, osteoporosis, and processes associated with aging. NRs bind specific sites on DNA and recruit cellular chromatin-modifying co-activators that engage the basal transcriptional machinery. However, NRs are not merely scaffolds for DNA and co-activators. They encompass multiple, distinct allosteric pathways that link the bound ligand to DNA (ligand↔DNA) and DNA to specific co-activators (DNA↔co-activator). Yet, the integrative complexity of NR allostery has impeded our understanding of its impact on gene expression. We are attempting to overcome these limitations with a combination of ligand-induced, residue-level structural and biophysical studies to identify allosteric pathways and link each allosteric phenomenon to specific DNA-binding sites.
Our primary research interests are concerned with the biological relevance of the 3-D structures of proteins. We were the first to determine the 3-D structures of the hormone-recognition domains of the constitutive androstane receptor (CAR) and of the thyroid- and retinoid-X-receptor (TR:RXR) complex by crystallography. CAR and TR have critical roles in the metabolic responses of the body against toxins and pharmaceutical drugs. Malfunctioning CAR is associated with tumors of the liver and mutations in TR are linked to developmental deficiencies, specifically with the attention-deficit hyperactivity disorder (ADHD).
In summary, we study (1) how distinct hormonal ligands control the DNA-binding specificity of NRs; (2) how DNA sequences control the recruitment of diverse co-regulators and (3) how distinct ligand-DNA-co-regulator complexes relate to discrete gene expression patterns. Our studies have the potential of establishing the molecular basis of nuclear receptor activity, determining the basis of NR malfunction and to predict the genome-scale effects of specific treatment regimens.
Selected publications (full list here):
- Fernandez EJ, Gahlot V, Rodriguez C, Amburn J. DNA-induced unfolding of the thyroid hormone receptor α A/B domain through allostery. FEBS Open Bio. 2017 May 15;7(6):854-864. doi: 10.1002/2211-5463.12229. eCollection 2017 Jun. pdf
- Mark Remec Pavlin, Joseph S. Brunzelle, and Elias J. Fernandez*. Agonist-Ligands Mediate the Transcriptional Response of Nuclear Receptor Heterodimers through Distinct Stoichiometric Assemblies with Coactivators. (2014) J. Biol. Chem. 289(36):24771-8. pdf
- Putcha, B.-D. K., Wright, E., Brunzelle, JS, and Elias J. Fernandez*. Structural basis for negative cooperativity within agonist-bound TR:RXR heterodimers. (2012) Proc Natl Acad Sci U S A., Apr 17;109(16):6084-7. pdf
- Wright, E., Busby, SA, Wisecarver, S., Vincent, J, Griffin, PR, and Elias J. Fernandez*. Helix 11 Dynamics is Critical for Constitutive Androstane Receptor Activity. (2011) Structure, Jan 12;19(1):37-44. pdf
- Putcha, B.-D. K. and Elias Fernandez*. Direct inter-domain interactions can mediate allosterism in the thyroid receptor. J. Biol. Chem. (2009) 21;284(34):22517-24. pdf
- Shan L, Vincent J, Brunzelle JS, Dussault I, Lin M, Ianculescu I, Sherman MA, Forman BM, Fernandez EJ*. Structure of the murine constitutive androstane receptor complexed to androstenol; a molecular basis for inverse agonism. Molecular Cell. (2004) Dec 22; 16(6):907-17. **Previewed in Cell Metabolism (2005) 1(1):6-8, Inaugural Issue. pdf