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Chip-on-chip, usually written ChIP-chip, is a method that combines chromatin immunoprecipitation (ChIP) with a DNA microarray to find where a protein binds across a genome. The DNA recovered by ChIP is read out by hybridization to probes on the array. It has largely been replaced by ChIP-seq, but array-era data are still in public repositories.
Short answer
ChIP-chip is ChIP read out on a microarray rather than by sequencing. Buck and Lieb describe it as ChIP coupled with whole-genome DNA microarrays to determine the spectrum of in vivo DNA binding sites for a protein. ChIP-seq, which sequences the immunoprecipitated DNA, offers higher resolution, less noise and greater coverage than its array-based predecessor (Park, 2009).
What ChIP-chip (chip-on-chip) is
What is a ChIP assay?
A ChIP assay uses an antibody to enrich the DNA that a protein of interest is bound to in cells, so that the enriched DNA can be identified. Massie and Mills note that the original ChIP identified binding at candidate loci using site-specific PCR and Southern blotting. That is a targeted, one-locus-at-a-time approach.
What is a ChIP-chip, or “ChIP ChIP”?
Pairing ChIP with genomic tiling arrays (ChIP-chip) allowed more unbiased mapping of binding across the genome rather than only at candidate sites (Massie and Mills, 2012). Buck and Lieb stress that the design and analysis differ significantly from locus-by-locus ChIP.
What is “DNA ChIP technology”?
The phrase usually means one of two things: a DNA microarray (the “chip”) or the ChIP assay itself. In the ChIP-chip method both are used together. For the array technology on its own, see the guide to DNA microarray analysis.
How the assay is used in practice
The workflow has two linked parts: immunoprecipitation of protein-bound DNA, then detection of that DNA by hybridization to an array whose probes tile the genome or selected regions. Because the readout is hybridization, the experimental design carries most of the weight. The Buck and Lieb review covers microarray design, the selection of controls, and the level of repetition (replication) required, with particular attention to mammalian and other large genomes. This page explains the method and does not give a bench protocol.
The wider ChIP family is covered in the guide to ChIP-seq, and antibody-based capture of protein complexes more generally in co-immunoprecipitation controls and interpretation. ChIP-seq profiles histone modifications as well as DNA-binding proteins (Park, 2009), a topic central to epigenetics.
ChIP-chip versus ChIP-seq
The comparison below follows Park (2009) and Massie and Mills (2012).
| Feature | ChIP-chip (array) | ChIP-seq (sequencing) |
|---|---|---|
| Resolution | Limited by hybridization uncertainty; tiling at high density needs many probes | Base-pair resolution, which Park calls perhaps the greatest improvement over ChIP-chip |
| Noise | Hybridization depends on GC content, length, concentration and secondary structure of target and probe; cross-hybridization between imperfect matches adds noise | Less noise than arrays |
| Genome coverage | Limited to the probes on the array; repetitive regions are typically masked out | Not limited by array probes |
| Cost at whole-genome scale | Tiling a large genome at high density needs many probes and is expensive | Already less expensive than ChIP-chip for high-resolution profiling of an entire large genome |
Where ChIP-chip still matters
- Reading older datasets. Studies from the array era remain part of the literature and may be deposited as array series in repositories such as the Gene Expression Omnibus. Knowing the probe design and masking helps in interpreting what such data can and cannot show.
- Targeted regions. Park states that, depending on genome size and the sequencing depth needed, a ChIP-chip experiment on carefully selected regions using a customized microarray may yield as much biological understanding as sequencing.
Common misunderstandings
- Chip-on-chip here means the genomics assay. On this page the term always means ChIP-chip, ChIP read out on a microarray.
- ChIP-chip is not ChIP-seq. Both start with immunoprecipitation; the readout, and therefore resolution, noise and coverage, differ.
- ChIP-chip is not locus ChIP. Its design and analysis differ significantly from candidate-locus ChIP (Buck and Lieb, 2004).
FAQ
How much does ChIP sequencing cost?
No price is given here. Park (2009) states that for high-resolution profiling of an entire large genome ChIP-seq is already less expensive than ChIP-chip, and that the comparison can change with genome size and the depth of sequencing needed.
Is chip-on-chip the same as ChIP-chip?
Yes. Both names refer to ChIP read out on a microarray.
Is ChIP-chip still used?
ChIP-seq gives more comprehensive occupancy surveys, with greater resolution and lower cost for whole-genome coverage (Massie and Mills, 2012), so it is the usual choice for new genome-wide work. Targeted custom arrays remain a documented option (Park, 2009).
Sources
- Buck MJ, Lieb JD. Genomics 2004;83(3):349-60. doi:10.1016/j.ygeno.2003.11.004. PMID 14986705. Checked 2026-11-07. https://pubmed.ncbi.nlm.nih.gov/14986705/
- Park PJ. Nat Rev Genet 2009;10(10):669-80. doi:10.1038/nrg2641. PMC3191340. Checked 2026-11-07. https://pmc.ncbi.nlm.nih.gov/articles/PMC3191340/
- Massie CE, Mills IG. Methods Mol Biol 2012;809:157-73. doi:10.1007/978-1-61779-376-9_11. PMID 22113275. Checked 2026-11-07. https://pubmed.ncbi.nlm.nih.gov/22113275/
