Thermodynamic stability of hydroxymethylcytosine (hmC) containing CpG repeats showed that though hmC destabilizes hypomethylated CpG, this effect can be reversed in a heavily methylated duplex. This dual-epigenetic modulation on duplex stability was also observed in cellular-mimic crowding conditions for both A-form DNA–RNA hybrids and B-form DNA–DNA duplexes.