GATA-dependent recruitment of MEF2 proteins to target promoters

The myocyte enhancer factor-2 (MEF2) proteins are MADS-box transcription fa ctors that are essential for differentiation of all muscle lineages but the ir mechanisms of action remain largely undefined. In mammals, the earliest site of MEF2 expression is the heart where the MEF2C isoform is detectable as early as embryonic day 7.5, Inactivation of the MEF2C gene causes cardia c developmental arrest and severe down-regulation of a number of cardiac ma rkers including atrial natriuretic factor (ANF). However, most of these pro moters contain no or low affinity MEF2 binding sites and they are not signi ficantly activated by any MEF2 proteins in heterologous cells suggesting a dependence on a cardiac-enriched cofactor for MEF2 action. We pro,ide evide nce that MEF2 proteins are recruited to target promoters by the cell-specif ic GATA transcription factors, and that MEF2 potentiates the transcriptiona l activity of this family of tissue-restricted zinc finger proteins. Functi onal MEF2/GATA-4 synergy involves physical interaction between the MEF2 DNA -binding domain and the carboxy zinc finger of GATA-4 and requires the acti vation domains of both proteins. However, neither MEF2, binding sites nor M EF2 DNA binding capacity are required for transcriptional synergy. The resu lts unravel a novel pathway for transcriptional regulation by MEF2 and prov ide a molecular paradigm for elucidating the mechanisms of action of MEF2 i n muscle and non-muscle cells.