We show that the looping mediated transcription activation by the combinatorial transcription factors (TFs) can be achieved via directional-dependent propulsion, tethered sliding and tethered binding-sliding-unbinding modes. In the propulsion mode, the first arrived TF at the cis-regulatory motifs (CRMs) further recruits other TFs via protein–protein interactions. Such TFs complex has two different types of DNA binding domains (DBDs) viz. DBD1 which forms tight site-specific complex with CRMs via hydrogen bonding network and the promoter specific DBD2s which form nonspecific interactions around CRMs. When the sum of these specific and cumulative nonspecific interactions is sufficient, then the flanking DNA of CRMs will be bent into a circle over the TFs complex. The number of TFs involved in the combinatorial regulation plays critical role here. When the site-specific interactions and the cumulative nonspecific interactions are strong enough to resist the dissociation, then the sliding of DBD2s well within the Onsager radius associated with the DBD2s-DNA interface towards the promoter is the only possible way to release the elastic stress of the bent DNA. The DBD2s form tight synaptosome complex upon finding the promoter via sliding. When the number of TFs is not enough to bend the DNA in to a circle, then tethered sliding or tethered binding-sliding-unbinding modes are the possibilities. In tethered sliding, the CRMs-TFs complex forms nonspecific contacts with DNA via dynamic loops and then slide along DNA towards promoter without dissociation. In tethered binding-sliding-unbinding, the CRMs-TFs performs several cycles of nonspecific binding-sliding-unbinding before finding the promoter. Elastic and entropic energy barriers associated with the looping of DNA shape up the distribution of distances between CRMs and promoters. The combinatorial regulation of TFs in eukaryotes has evolved to overcome the looping energy barrier.