Zeb1 and Tle3 are key regulators of muscle differentiation

Our skeletal muscle is made up of large, elongated cells with multiple nuclei, known as myofibers. Myofibers arise by a process known as differentiation, where stem cells become specified to the muscle specific fate, fuse with each other and assemble the contractile protein machinery required for muscle contraction. One such crucial muscle contractile protein is myosin heavy chain-embryonic (MyHC-embryonic), encoded by the Myh3 gene. MyHC-embryonic is expressed during embryonic development and absent in adult life except during muscle regeneration associated with injury or disease. How MyHC-embryonic expression is regulated in such a precise manner is unclear.

In this study, we find that the Zinc-finger E-box binding homeobox 1 (Zeb1) and Transducin-like Enhancer of Split 3 (Tle3) are crucial proteins that interact with each other and differentially regulate Myh3 expression. We uncover a novel enhancer upstream of Myh3 promoter that is bound by Zeb1 to regulate Myh3 expression. Tle3 and Zeb1 have opposing effects in muscle formation, with Zeb1 function decreasing differentiation and Tle3 promoting differentiation. We also identify that Tle3 functions upstream of Zeb1 in regulating differentiation. Thus, we have uncovered a novel molecular mechanism by which muscle differentiation and Myh3 expression are regulated, which is of importance in muscle regeneration following injury and in muscle diseases such as Duchenne muscular dystrophy.

Kumar, P., Zehra, A., Saini, M., and Mathew, S. J. (2023). Zeb1 and Tle3 are trans-factors that differentially regulate the expression of myosin heavy chain-embryonic and skeletal muscle differentiation. FASEB Journal 37(8):e23074. doi: 10.1096/fj.202201698RR.

Image legend:

Mouse myoblast cells treated with a control siRNA (left) or Zeb1 siRNA (right), differentiated for 5 days, labeled using a mixture of myosin heavy chain antibodies (Red) and DAPI (Blue). Increased differentiation marked by more number of myosin heavy chain labeled myofibers are seen upon Zeb1 knockdown.