Well, I felt like bringing up "the bubble" mainly for it's implications about an indeterminate "when." What Ferne said about Simpsons time still technically holds true (still year 0), but we now have a much better understanding of what Yoshida meant at PAX East when he talked about the storyline being split into "seasons."
2.0's content is from season 1, and thus all takes place before the season finale "Before the Dawn." There are even some stray hints towards stories (mainly Coil) happening before you do them. No spoilers, of course, just enough to make you wonder if and when you do lack context.
Players getting around to leveling CUL afterwards will get multiple hints about it's place in overall MS chronology, the most obvious happening when we don't even consider poisoning Lolorito at level 30. And at level 50?
(Fringe season 2 spoilers):
Nanamo's just pulling a Charlie Francis.
For everyone else, time will tell. Some really good stories still manage to get away with only one or two game changing deaths near the beginning and never feel the need to kill anyone else off, because death has served its purpose. If nothing else, this will make Merlwyb's action scenes that much more gripping, simply by knowing that she could die, even if she never actually does.