The principle of ChIP-chip is simple. The first step is to cross-link the protein-DNA complex. This is done using a fixating agent, such as formaldehyde. The cross-linking can later be reversed with heat. Cross-linking kills the cell, giving a snapshot of the bound TF at a given time. The cell is then lysed, the DNA sheared by sonication and the chromatin[2] (TF-DNA complexes) is pulled down using an antibody (i.e. immunoprecipitated). If an antibody for the TF is available, then it is used; otherwise, the TF is tagged with an epitope targeted by commercially available antibodies (the latter option is cheaper, but runs the risk of altering the TF's functionality). Cross-linking is then reversed to free the bound DNA, which is then amplified, labeled with a fluorophore and dumped onto a DNA-array. The scanned array reveals the genomic regions bound by the TF. The resolution is around ~500 bp as a result of the sonication step.

The DNAse foot-printing method starts by focusing on a given region of interest (e.g. a promoter region) and amplifying it by PCR to obtain lots of sample. It then throws in the TF and then the DNAse. The mix is left to stir for a short time and then gel electrophoresis is run to compare the pattern of fragments in a control (no TF) and in the sample. If the TF has bound the sample, it will have protected a stretch of DNA (encompassing some fragments of the control) and thus those fragments will not appear in the sample gel. The fragments can then be cut-out from the gel, purified and sequenced to obtain the sequence of the protected region. This is often used to identify the binding motif of a TF for the first time. The foot-printing will typically resolve the protected region down to 50-100 bp, and the sequence can be then examined for possible TF-binding sites either by eye of using a computer search.

MSA can be used to align promoter regions and highlight regions of conservation that may be indicative of transcription factor binding sites.