hDREF, a MEF2 sensitive regulator of DNA synthesis

Abstract

The Myocyte Enhancing Factor 2 (MEF2) family of proteins have been implicated in a wide variety of cellular mechanisms including: muscle and neuronal differentiation, inhibition of apoptosis, upregulation of c jun expression, and embryonic and post-natal cardiac development. In the course of my research I have identified a novel MEF2-responsive gene referred to as h&barbelow;uman D&barbelow;NA R&barbelow;eplication Related E&barbelow;lement F&barbelow;actor (hDREF). Three putative MEF2 consensus-binding sites have been found within the two untranslated regions (UTRs) of the hDREF sequence (which lie 5' and 3' to the open reading frame). Using CHromatin I&barbelow;mmunolP&barbelow;recipitation (CHIP) assays I have shown that MEF2 proteins associate with the MEF2 binding site found within the 5'UTR of hDREF under both growth and differentiation conditions. Furthermore, mutation of the MEF2 binding sites results in a failure to repress expression, which indicated that MEF2 acts to negatively regulate hDREF expression during differentiation. Endogenous expression studies indicate that hDREF is highly expressed during growth and downregulated during differentiation. Functional studies suggest that hDREF is directly involved in regulating DNA synthesis, and that overexpression of hDREF leads to aberrant DNA replication in post-mitotic cells leading to polyploidy. Based on my research I propose that hDREF represents a novel MEF2 regulated gene, and that the primary function of hDREF is to ensure DNA synthesis with the cell cycle.