Huge region up in USA is Appalachia (4)
I believe the answer is:
asia
'huge region' is the definition.
(I've seen this before)
'up in usa is appalachia' is the wordplay.
'up' shows that the letters should be reversed in order (in down clue: letters go upwards).
'in' indicates a hidden word.
'aisa' is hidden in the letters of 'usa is appalachia'.
'aisa' back-to-front is 'ASIA'.
(Other definitions for asia that I've seen before include "Part of the world" , "group of countries" , "A great deal of land" , "Populous continent" , "Earth's largest continent" .)