I have two ChIP-seq tracks of a histone modification from WT and KO cells which have been processed in parallel. I also have input tracks for both samples. The histone modification is diffuse across the genome and does not form clear peaks. Peak calling is therefore very difficult. Normally, to identify novel binding sites, I would call peaks on WT and KO samples individually and then intersect the two peak files.

In this case, I am considering calling peaks on the KO sample using the WT sample as my "input" to identify novel regions of enrichment.

Both the ChIP samples and the matched inputs are similar to each other with comparable read counts.

Are there any reasons why this would be a bad idea?