Theoretical analysis of confinement mechanisms for epigenetic modifications of nucleosomes

Abstract

Nucleosomes and their modifications often facilitate gene regulation in eukaryotes. Certain genomic regions may obtain alternate epigenetic states through enzymatic reactions forming positive feedback between nucleosome states. How a system of nucleosome states maintains confinement is an open question. Here we explore a family of stochastic dynamic models with combinations of read-write enzymes. We find that a larger number of intermediate nucleosome states increases both the robustness of linear spreading in models with only local recruitment processes and the degree of bi-stability under conditions with at least one non-local recruitment. Further, supplementing the positive feedback with one negative feedback acting over long distances along the genome enables effective confinement of epigenetic, bistable regions. Our study emphasizes the importance of determining whether each particular read-write enzyme acts only locally or between distant nucleosomes.

Two-way feedback between chromatin compaction and histone modification state explains Saccharomyces cerevisiae heterochromatin bistability

“…However, it remains to be explored how robust this is with respect to cell-cycle-dependent processes other than DNA replication, such as genome-wide acetylation changes ( 55 ). Another limitation of this work was the isolated description of the HMR locus in the model: placing the locus in the context of the chromosome and comparing the regulation of the locus with that of other (possibly active) genes would yield valuable insights ( 56 ). Furthermore, if more detailed measurements of the conformation of the locus were available, a more ambitious physical modeling could be attempted ( 19 , 37 ), which would most likely improve the predictive power of the model.…”

Two-way feedback between chromatin compaction and histone modification state explainsS. cerevisiaeheterochromatin bistability

“…However, it remains to be explored how robust it is with respect to cell-cycle dependent processes other than DNA replication, such as genome-wide acetylation changes (Wilkins et al, 2014). Another limitation of this work was the isolated description of the HMR locus in the model: placing the locus in the context of the chromosome and comparing the regulation of the locus with that of other (possibly active) genes would yield valuable insights (Nickels & Sneppen, 2023). Finally, if more detailed measurements of the conformation of the locus were available, a more ambitious physical modelling could be attempted (Farr et al, 2021), which would most likely improve the predictive power of the model.…”

Role of diffusion and reaction of the constituents in spreading of histone modification marks

“…If modifications can spread to all proximal nucleosomes in 3D, it is not clear exactly how a modification limits itself into domains of finite size. Some hypotheses have been proposed to address this question; they include having boundary elements that slow down the spreading [ 31 , 54 , 57 , 62 ], looping mechanisms that relax chromatin quicker [ 55 – 60 ], the possibility of multiple intermediate states [ 63 ], the presence of large gaps between sliding nucleosomes [ 64 – 68 ], and enzyme limitation [ 61 , 69 ].…”