TL:DR: Take the futuristic 1950s world BEFORE the fallout, and flesh that out more, maybe in the form of The Sims.
I really loved the way the world before the Fallout looked in Fallout 4 in the beginning of that Fallout 4 E3 gameplay video they showed off yesterday. The combination of the 1950s and future technology just looks so interesting. The beginning of this trailer made me really want to explore that world maybe even more than the world post-fallout.
I think Bethesda should develop a competitor to The Sims. Bethesda has always been good at developing open world games that are similar to it, with games such as Skyrim. Of course, Skyrim is an RPG with combat, but who says the competitor to The Sims can't be a bit more interesting?
The Sims franchise is pretty much now failing thanks to EA of course, and Bethesda would clearly be able to become king of the genre The Sims once was with their awesome ideas -- even The Sims' fans are asking for Bethesda to try making a competitor. Setting alone, and incorporating a lot of those before-Fallout themes would work so well and grab so many players due to curiosity alone.
What do you think? Based on the E3 trailer I saw showcasing the awesome character customization, the huge amount of voice acting they put into the game alone, etc., their experience with huge, open worlds, and the setting of a futuristic 1950s, I think it'd work very well.