Well I will try to break down some of it from a feasibility perspective. I try to go for FFP/status with I use the most, alliance are nice but in the end, your home airline is going to protect its own elite before other ones

DL-Hub at ATL which you'll be flying often, potentially easier domestic upgrades but hard to use to almost worthless miles from what I hear, analogy of the 20's German mark isn't far off and you might want to use those PMU to start your stoves too.
CO-Hub at EWR, and you said you like the TXL flights, from the CO board, some fuel stop issues in winter. They also run CO brand bus service which can help you add up segments rather easily but harder upgrades.
US-Hub at PHL/CLT, I think you might be underlooking it here. With TYS and ATL, you do have connecting flights from ABE to CLT, or in the case of ATL, direct from PHL. CLT works great with flights in the SE especially if it helps you avoid the northeast mess and I think upgrades chances are pretty good on US, getting them that is, not service.
UA-Hub at IAD, similar to US although you lose that non-stop to ATL when you really need it, starnet blocking
AA-Closest hub at ORD, valuable miles but not really an option for you unless you really want to pad up your account


If I were you and timing(or saving them) was my top priority, I'll go with US.
Ya their 1st class sucks
Both EWR and PHL will have enough delays to annoy you, trust me on that one! Slept at an airport as a 16 y.o because of EWR.
But in the end, you have more outs/options, either connecting in CLT from ABE on mainline and if the weather goes bad, non-stop from PHL.

Hope that helps a bit, if you were looking from a different perspective, please said so as the outlook can be completely different.