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Epigenetic control of chromatin structure -
Solving an intertwined puzzle with a specialized coarse-grained model

Final Report Summary - EPICHROMATIN (Epigenetic control of chromatin structure - <br/>Solving an intertwined puzzle with a specialized coarse-grained model)

This project analyzed the effects of histone tail epigenetic modifications in chromatin behavior by using state-of-the-art biomolecular simulation techniques. Understanding chromatin structure and its control by acetylation is a strategic academic priority. Eukaryotic DNA is packed together with histone and non-histone proteins in compact and dynamic chromatin structures. Changes in chromatin organization – for instance those induced by acetylation – are intimately linked to regulation of fundamental template-directed functions such as DNA transcription, replication, and repair. Chromatin compaction is promoted by nucleosome-nucleosome interactions, which are established between the N-terminal regions of the histone proteins and other chromatin components (i.e. linker DNA and other nucleosomes). These histone tails contain an enormous number of sites for epigenetic modifications, such as acetylation and phosphorylation, some of which alter chromatin structure and DNA accessibility. While it has been suggested that epigenetic modifications might regulate histone tail function by increasing the stability of flickering folded states, with respect to unfolded conformations, the mechanism by which epigenetic modifications regulate tail function remains elusive. To determine whether histone tails exhibit transient order when part of the nucleosome, and when involved in internucleosome interactions, in this project we performed massive all-atom simulations of the tails in different environments (isolated tails: 27-μs REMD, tails in contact with nucleosomal DNA: 16-μs REMD, tails in contact with nucleosomal and linker DNA: 2-μs REST2, and tails within dinucleosome complexes: 2-μs MD), as well as coarse-grained simulations of 24-mer chromatin fibers with different states of folded tails. In addition, we compared the behavior of native versus different H4/H3 Lys-acetylated tails. Our results demonstrated that histone tails have a small propensity to form secondary structural elements, which increases by the presence of mono-acetylation. We also found that the presence of DNA destabilizes the formation of beta-sheet motifs, notably decreasing the overall content of residues with secondary structural elements. In addition, our dinucleosome simulations showed that although H4 lys-16 acetylation does not alter the affinity of the tail to contact the DNA, it decreases its ability to establish fiber compacting internucleosome interactions by 238%. Finally, our Monte Carlo simulations of a chromatin coarse-grained model demonstrate that tail disorder is required for maximum chromatin compaction, and that even a small presence (10%) of compact histone tails triggers fiber opening. These results might help explain how by limiting the histone tails ability to establish chromatin-compaction internucleosome interactions, acetylation of histone tails can induce deregulation of gene expression. These results can be of interest to a wide-range of beneficiaries including molecular biologists and biophysics, and have the potential to help advance the frameworks used to understand diseases related to aberrant gene expression, such as multiple sclerosis, diabetes, and cancer.
Transfer of knowledge to the host was achieved through the work in partnership between Dr. Collepardo and one PhD student and one research assistant to produce a server for the analysis of nucleic acid properties across scales, for which Dr. Collepardo offered her expertise in low resolution DNA coarse-grained modelling. Transfer of knowledge was also achieved through an ongoing collaboration between a current postdoc in the host group, specialised in all-atom modelling of biomolecuels, and Dr. Collepardo, expert in coarse-grained chromatin modelling, who have joined efforts to characterise the effects of histone tail epigenetic modifications and its implications in chromatin structure. Knowledge transfer at the international level was achieved through a new research collaboration between the host group and New York University (Schlick group). An additional avenue for continuous transfer of knowledge as been open through a new collaboration that will be established between the host group and the University of Cambridge (where Dr. Collepardo is now based).

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