Structure and functions of powerful transactivators: VP16, MyoD and FoxA

Abstract

Induced pluripotent stem cell (iPSC) technology is a promising approach for converting one type of a differentiated cell into another type of differentiated cell through a pluripotent state as an intermediate step. Recent studies, however, indicate the possibility of directly converting one cell type to another without going through a pluripotent state. This direct reprogramming approach is dependent on a combination of highly potent transcription factors for cell-type conversion, presumably skipping more physiological and multi-step differentiation processes. A trial-and-error strategy is commonly used to screen many candidate transcription factors to identify the correct combination of factors. We speculate, however, that a better understanding of the functional mechanisms of exemplary transcriptional activators will facilitate the identification of novel factor combinations capable of direct reprogramming. The purpose of this review is to critically examine the literature on three highly potent transcriptional activators: the herpes virus protein, VP16; the master regulator of skeletal muscle differentiation, MyoD and the "pioneer" factor for hepatogenesis, FoxA. We discuss the roles of their functional protein domains, interacting partners and chromatin remodeling mechanisms during gene activation to understand how these factors open the chromatin of inactive genes and reset the transcriptional pattern during cell type conversion.

Fig. 1. Domain structure and interacting proteins of herpes virus protein VP16

(A) Domain structure of VP16. The amino acid number for the TAD sequence varies slightly depending on the literature source. The numbers used here were taken from Walker et al. (Walker et al., 1993). (B) Proteins that interact with VP16 during gene activation.

Fig. 2. Domain structure and functions of MyoD

(A) Structure and functions of MyoD domains. Amino acid numbers are shown above the protein domains. Amino acids numbers are taken from Bergstrom and Tapscott (Bergstrom and Tapscott, 2001; Gerber et al., 1997). (B) Recruitment of binding proteins and resulting chromatin relaxation by MyoD during gene activation.

Fig. 3. Domain structure of FoxA and its function as a pioneer factor

(A) Domain structure of FoxA2. FoxA1 and A3 share similar structures. The amino acid number for the carboxyl terminus sequence varies depending on the literature source. The numbers used here were taken from Qian and Costa. (Qian and Costa, 1995). (B) Replacement of the linker histone H1 by FoxA and subsequent relaxation of chromatin during gene activation.