I would like to see FO 4 in someplace like Missouri, with a huge map. What I think they could do with this is make the game centralize along the river. Not like the other games, but focus on a trade network between Jefferson City, St. Louis, and Kansas City. Jefferson City would be a small, semi powerful, very rich city, kinda like Venice (Maybe?). Kansas City will be a two faction split, not in a conventional war, but fighting with assassinations, and other different, sabotage style of warfare. And St. Louis would have many gangs fighting over the main city, with one powerful group holding the coast of the river, controlling the trade. And you could also travel to the landlocked towns to see how they develop in comparison. And instead of having a standard, main quest, You can do major, mega quests, which will have a dynamic effect on the world. Say one time you help clear out a group of river pirates from Jefferson city, and say this takes a few hours cause they are supported by the guys who you helped JC fight earlier, BUt in another game, you clear them out in a few minutes because they are a group of poor farmers who were repressed by say... Columbia, who dabbles in slave trade with Kirksville, and has been raiding farms to provide slaves for restoration work because a gang you helped blew up part of an important wall. And this is all effected by things that you do in the game, and each time you start the game there is a new starting situation. Maybe 4-5. Which also help decide how the game plays out.
TLDR: Wont happen...