DREME is a tool for discovering short regular expression motifs which are enriched in the provided dataset. It is limited to working in DNA as the large combination space for amino acids makes DREME's approach unfeasable. DREME also has the capability to use two datasets to find motifs which are enriched in one when compared to the other.
Note the following referrs to the sequence set in which you are finding motifs in as the positive sequences and to the comparative sequence set as the negative sequences.
DREME works best with lots of short (~ 100bp) sequences. If you have a couple of long sequences then it might be benificial to split them into many smaller (~ 100bp) sequences. With ChIP-seq data we recommend using 100bp regions around the peaks.
DREME always uses a comparative sequence set but you don't have to supply it as DREME can create it by using di-nucleotide shuffling. If you wish to use your own sequence set then there are a few guidlines you should follow.
The sequence lengths of the comparative sequences should be roughly the same as the sequences to search for motifs. This is because the null model assumes that the probability of finding a match in a sequence in either sequence set will be roughly the same for an uninteresing motif. If the comparative sequences are longer this provides more locations that the motif could match making it more likely it will match and hence skewing the p-value calculations possibly excluding a motif you would be interested in.