Recent studies of several multigene clusters have shown that gene activation by a remote enhancer is associated with chromatin loop formation. It is not fully understood how a chromatin loop forms in a nucleus or how it is involved in gene regulation. In this article, we propose that the major feature that determines loop formation is the flexibility of chromatin, and that this flexibility is modulated by histone acetylation (and other modifications). Thus, histone modifications will modulate distribution of the preferential looping site in chromatin, which, in turn, determines the probability of interaction between a remote enhancer and the cognate genes. This model can explain gene expression changes in the Hoxd gene cluster and the beta-globin locus.