HDAC4 Post-Translationally Modifies RUNX2 Inhibiting the Osteoblast Differentiation Pathway during Iron Deficiency

Chronic kidney disease (CKD) affects millions of Americans and patients frequently incur bone loss and iron deficiency. My research focuses on the intersection of these two co-morbidities. Histone deacetylase 4 (HDAC4) is responsible for deacetylating other proteins within the cell including histones, signaling molecules, and transcription factors. Runt related transcription factor (RUNX2) is the critical transcriptional driver of osteoblast differentiation, the bone forming cell. From preliminary research, when an iron chelator (Deferoxamine) is added to cells, HDAC4 is increased coinciding with decreases in osteoblast differentiation markers despite no decrease in RUNX2. As HDAC4 has been noted to interact with RUNX2, I hypothesize under iron deficient conditions HDAC4 is responsible for modifying RUNX2 which blunts DNA binding, thereby decreasing osteoblast differentiation. To test this hypothesis, I will complete co-immunoprecipitations to determine the level of RUNX2 acetylation as well as RUNX2 and HDAC4 interactions in iron deficient conditions over time. I will also conduct DNA-RUNX2 immunoprecipitations to evaluate DNA binding capabilities in these conditions. Thus, understanding the molecular mechanism of iron deficiency decreasing osteoblast differentiation will elucidate novel targets of therapeutic interventions to improve bone parameters for patients suffering from chronic iron deficiency, especially in CKD.

Supervisor: Dr. Erica Clinkenbeard 
Department: Medical and Molecular Genetics