Huge region over in USA is Appalachia (4)
I believe the answer is:
asia
'huge region' is the definition.
(I've seen this before)
'over in usa is appalachia' is the wordplay.
'over' says the letters should be written in reverse.
'in' says the answer is hidden in the clue.
'aisa' is hidden in the letters of 'usa is appalachia'.
'aisa' reversed gives 'ASIA'.
(Other definitions for asia that I've seen before include "Thailand and its location" , "The Orient" , "One-third of all land" , "group of countries" , "Continent of the Hindu Kush" .)