**5. Conclusion**

COMBO-FISH offers a highly variable toolbox of labeling combinations and strategies for chromatin architecture and bio-medical research. Here we have introduced

three strategies: (a) Design of a COMBO-FISH probe set which consists of several oligonucleotide probes that *specifically co-localize* at a given genome target as for instance, a tumor-relevant gene that could be involved in gene copy number changes or tumor-inducing translocations. (b) Design of a COMBO-FISH probe set which consists of one oligonucleotide probe which *in many copies specifically co-localize* at a given genome target as for instance a centromere. (c) Design of a COMBO-FISH probe set which consists of one oligonucleotide probe that *uniquely occurs* at several given repetitively occurring genome targets only as for instance SINEs or LINEs. The efficiency of the probe set can be further enhanced by incorporating structural [51–53] and dynamical parameters determined by molecular dynamics simulations (e.g., AMBER [54–56], GROMOS [57, 58], CHARMM [59, 60]) into the probe design, which we currently investigate.

In combination with super-resolution localization microscopy and novel tools of data evaluation and interpretation by geometric and topological algorithms [61–64] COMBO-FISH probes offer new perspectives in understanding the reaction of chromatin as a system as a whole during gene expression, proliferation, or stress response [47].
