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I'm currently investigating ChIP-seq vs. ChIP-exo for finding binding sites.

As far as I can tell, ChIP-exo seems to be better in every way than ChIP-seq... but then again, I'm not strong in this area.

Are there any weaknesses in the ChIP-exo approach?

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just as a first pass I'd say the extra ligation and primer addition steps for CHP-exo might resolve fewer hits in a given run, though that might also make your results less noisy as well. –  shigeta Jun 6 '12 at 13:54

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ChIP-exo does seem to be the "ChIP-seq killer." I've seen Dr. Pugh present it a few times, and the audience is pretty much always impressed.

One thing I'd do if I were of the "experimental bent" would be to add random degenerate barcodes in the library prep to control for potential PCR artifacts. I imagine that since the "peaks" in ChIP-exo seem to be quite a bit narrower than ChIP-seq, I reckon it'd harder to use some coverage-in-local-neighborhood to remove such biases (assuming you wanted to do so).

To give you an idea of what I'm thinking of -- it would be somehow similar to what is depicted here.

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