THE BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR MIST1 FUNCTIONS AS A TRANSCRIPTIONAL REPRESSOR OF MYOD

A good model system to examine aspects of positive and negative transc riptional regulation is the muscle-specific regulatory factor, MyoD, w hich is a basic helix-loop-helix (bHLH) transcription factor. Although MyoD has the ability to induce skeletal muscle terminal differentiati on in a variety of non-muscle cell types, MyoD activity itself is high ly regulated through protein-protein interactions involving several di fferent cofactors, Here we describe the characterization of a novel bH LH protein, Mist1, and how it influences MyoD function, We show that M ist1 accumulates in myogenic stem cells (myoblasts) and then decreases as myoblasts differentiate into myotubes, Mist1 functions as a negati ve regulator of MyoD activity, preventing muscle differentiation and t he concomitant expression of muscle-specific genes. Mist1-induced inhi bition occurs through a combination of mechanisms, including the forma tion of inactive MyoD-Mist1 heterodimers and occupancy of specific E-b ox target sites by Mist1 homodimers. Mist1 lacks a classic transcripti on activation domain and instead possesses an N-terminal repressor reg ion capable of inhibiting heterologous activators, Thus, Mist1 may rep resent a new class of repressor molecules that play a role in controll ing the transcriptional activity of MyoD, ensuring that expanding myob last populations remain undifferentiated during early embryonic muscle formation.