It should take place after the Vault 101 Dweller's journey but in a more evolved DC.
I hope, given the righteous slaughter of the Super Mutants at the hands of the Vault 101 Dweller, that the remaining few Super Mutants once again become enemies to fear and not just mindless grunts. Instead of having the classes of Super Mutants they should stay more true to Fallout 1's mutants.
Everything that the Vault 101 Dweller could have affected in Fallout 3 should be modified in such a way that the new world can generalize what happened. What I mean is, for instance:
[spoiler:0196a150ae]You can choose to kill the Ghouls for the Tenpenny residents or you can help the Ghouls, which ends up meaning the extinction of the normal humans in the tower. The new protagonist should see Tenpenny tower as the center of a battleground between Ghouls and humans fighting for it, king of the hill style. The good karma choice allowed the Ghouls to assimilate into the group of humans but eventually drive the humans away, whereas the bad karma choice meant the extinction of the Ghouls in the tunnels nearby. Word would spread that would anger either the humans or the Ghouls outside of this area to fight for this landmark and claim it as their own, or something like that. I hate how the main struggle is in downtown DC and nowhere else; I hope there are many skirmishes and battles happening all over the place.
Another example is Megaton. In the new protagonist's eyes, Megaton should have been destroyed. No one will know how it happened exactly, but it was destroyed by either a nuclear blast based off the bad karma choice or an Enclave invasion based off the good karma choice (they found out you live there so they tried to look for you and killed everyone and looted and destroyed the place).[/spoiler:0196a150ae]
The new expansion should still stay in DC, except with various changes that take into account all the possible path taken and decisions made by the Vault 101 Dweller. Enclave should not exist, Super Mutants should be insanely tough without the need for four classes of them (all of them should be Master-level tough), and BoS should have a civil war between the brothers and the outcasts that taken Lyons out of power and revert the Brotherhood to it's technology scavenging ways. Power Armor should be improved as a result.