Histone tails cooperate to control the breathing of genomic nucleosomes

Abstract

Genomic DNA is packaged in chromatin, a dynamic polymer that forms fibers variable in size and compaction. Chromatin's monomeric unit, the nucleosome, is formed by wrapping ~ 146 basepairs of DNA around histone proteins. Dynamic transitions in the chromatin structure, which depend on intra- and inter-nucleosome dynamics and on chemical modifications of histones, are key to initiating gene regulation programs. The histone modifications occur in unstructured terminal regions known as tails and are key to epigenetic regulation of gene expression. Here we elucidate how the interplay between the tails of two histones, H3 and H2A modulate ample breathing motions of genomic nucleosomes. From 18 μs of atomistic molecular dynamics simulations of two genomic and one engineered nucleosomes, we observed two rare, large opening events, one in each genomic nucleosome, and only small amplitude breathing in the engineered nucleosome. Clustering of the sampled structures revealed a strong correlation between DNA conformations with different degree of opening and histone tail conformations and positions. The ample nucleosome motions were caused by changes in the interaction profiles between the DNA and clusters of lysine and arginine residues in these tails, many of which are targets for epigenetic regulatory modifications. Given that histone tail modulated nucleosome breathing can change the structure and compaction of chromatin fibers, the mechanism we describe provides the basis for understanding chromatin dynamics at atomic resolution.

OCT4 interprets and enhances nucleosome flexibility

“…The position and conformation of the H3 and H2AC tails are critical for nucleosome breathing (25,34,35). We proposed that substantial, short lived opening of free nucleosomes is only possible when these tails establish a minimum number of interactions with the linker DNAs (25). Here we also observed that the long lived Oct4 mediated nucleosome opening depends on the mobility of histone tails.…”

“…This demonstrates that the configurations of the H3 and H2AC tails are crucial for the initial nucleosome opening in the presence of Oct4. We recently showed that these tails modulate the intrinsic breathing of free nucleosomes (25). Taken together, our findings indicate that Oct4's ability to stabilize open nucleosome conformations depends on the nucleosome structural flexibility induced by histone tail mobility.…”

“…We also showed that both genomic nucleosomes open transiently in the µs long simulations of free nucleosomes (19,25). The opening was dependent on histone tail conformations and was not observed in simulations of an engineered nucleosome sequence (Widom 601).…”

“…For the LIN28B nucleosome, crosslinking slightly enhanced binding at low Oct4 concentrations but reduced binding at high concentrations (Figure 2A). This can be explained by the free LIN28B nucleosome adopting more open conformations (19,25).…”

“…Histone tails regulate inter-and intra-nucleosome dynamics (30). We recently reported in a manuscript currently under peer review that the positions and conformations of histone tails modulate nucleosome breathing (25). Therefore, we characterized how Oct4 binding modifies the interaction of histone tails with the DNA.…”