Histone N-tails modulate sequence-specific positioning of nucleosomes

Spatial organization of chromatin is essential for cellular functioning. However, the precise mechanisms governing sequence-dependent positioning of nucleosomes on DNA remain unknown in detail. Existing algorithms, considering the sequence-dependent deformability of DNA and its interactions with the histone globular domains, predict rotational setting of only 65% of human nucleosomes mapped in vivo. To uncover additional factors responsible for the nucleosome positioning, we analyzed potential involvement of the histone N-tails in this process. To this aim, we reconstituted the H2A/H4 N-tailless nucleosomes on human BRCA1 DNA (∼100 kb) and compared their positions and sequences with those of the wild-type nucleosomes. We found that removal of the histone N-tails promoted displacement of the predominant positions of nucleosomes, accompanied by redistribution of the AT-rich and GC-rich motifs in nucleosome sequences. Importantly, most of these sequence changes occurred at superhelical locations (SHLs) ±4, ±1, and ± 2, where the H2A and H4 N-tails interact with the DNA minor grooves. Furthermore, a substantial number of H4-tailless nucleosomes exhibit rotational settings opposite to that of the wild-type nucleosomes, the effect known to change the topological properties of chromatin fiber. Thus, the histone N-tails are operative in the selection of nucleosome positions, which may have wide-ranging implications for epigenetic modulation of chromatin states.