A theoretical model of how the rotational setting of a nucleosome may facilitate its own disassembly by EP300 acetylation. (a) RNA pol II (Pol II) after transcription initiation at the TSS (black arrow). Our model is consistent with Pol II that is paused at this stage, although this is not a requirement. (b, c) Subsequent steps leading to elongation if the nucleosome is rotationally constrained (b), and the process for fuzzier nucleosome positioning (c). In (b), red triangles indicate the positions of two RR dinucleotides at a distance multiple of 10 bp from the TSS. Several hundred promoters carrying such a signal in the human genome would generate the pattern shown in Figure 2a. On a given sequence, this may be sufficient to constrain the +1 nucleosome to remain set at a specific position and thus at a specific rotational angle with respect to the advancing Pol II. After binding to its DNA recognition site and/or being recruited by other proteins, EP300 binds to Pol II and is now optimally located in space to deposit acetylation marks on the +1 nucleosome. These may include several targets on histone tails but critically includes H3K56 located on the globular part of H3 (orange circle), required for tipping the nucleosome assembly/disassembly equilibrium towards disassembly. Next, Pol II is free to engage in the elongation phase. In (c), RR dinucleotides occur randomly in the sequence and the +1 nucleosome may therefore adopt any rotational angle. Shown here are three possible nucleosome locations (+0, +1 and +5 bp from the position shown in (b)), each with a different angle. For instance, a 5-bp shift equivalent to half the helical pitch would rotate the nucleosome by approximately 180° with reference to the position at +0 bp, as shown in Figure 4. Depending on the nucleosome angle, EP300 is not optimally located with respect to its target and needs to search or probe for its histone target, thus delaying H3K56 acetylation and subsequent nucleosome disassembly.