The myocyte-specific enhancer factor-2 (MEF2) proteins are expressed in the three major types of muscle (skeletal, cardiac, and smooth) and function as transcriptional activators of muscle-specific and growth factor-regulated genes through binding to a canonical A/T-rich cis-element. Although MEF2 proteins are also expressed in brain, MEF2-regulated muscle-specific gene products are not detected in this tissue. To gain insight into the regulation of MEF2 function in vivo, we have selected its optimal DNA targets from a library of degenerate oligonucleotides using anti-MEF2A antibodies and cell extracts from skeletal muscle, heart, and brain. The consensus binding site in these three tissues contains an indistinguishable core motif, 5`-CT(A/t)(a/t)AAATAG-3`. However, the optimal target for MEF2 expressed in the brain shows additional sequence constraints (5`-TGTTACT(A/t)(a/t)AAATAGA(A/t)-3`) that are not observed in the sequences selected with skeletal and cardiac muscle extracts. Thus, differences in DNA binding preferences of MEF2 proteins in muscle and brain may contribute to tissue-specific gene expression during myogenesis and neurogenesis.

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