I think it will help, it will show that you just went through a training program, you haven't gone stale, and you have drive.
Majors hire from regionals all the time. I doubt a major will look at you unfavorably for working at a regional. I think it will mainly be a hit to the ego, and feeling like you are taking a step in the wrong direction. I'm in the hiring pool for two regionals, but giving the stiff arm at the moment. Especially considering that I can make a years salary there in about two months of active duty pay.
At some of the various majors, I have heard stories about Chief pilots that had a real bug about getting 121 time. The only thing is I'm not sure how much weight they assign to 121 FO time.
A website to check out:
Interline Travel and Pass Travel Information for airline employees - passrider.com - Interline Travel and Pass Travel Information for airline employees, retired airline employees and their families and friends. Think of it as a misery meter, and look at the commute to each of the possible domiciles. My biggest take away from an Interview at a regional is how bad a two leg commute sucks.