Chromatin computation: Epigenetic inheritance as a pattern reconstruction problem

Abstract

Eukaryotic histones carry a diverse set of specific chemical modifications that accumulate over the life-time of a cell and have a crucial impact on the cell state in general and the transcriptional program in particular. Replication constitutes a dramatic disruption of the chromatin states that effectively amounts to partial erasure of stored information. To preserve its epigenetic state the cell reconstructs (at least part of) the histone modifications by means of processes that are still very poorly understood. A plausible hypothesis is that the different combinations of reader and writer domains in histone-modifying enzymes implement local rewriting rules that are capable of "recomputing" the desired parental modification patterns on the basis of the partial information contained in that half of the nucleosomes that predate replication.To test whether such a mechanism is theoretically feasible, we have developed a flexible stochastic simulation system (available at http://www.bioinf.uni-leipzig.de/Software/StoChDyn) for studying the dynamics of histone modification states. The implementation is based on Gillespie's approach, i.e., it models the master equation of a detailed chemical model. It is efficient enough to use an evolutionary algorithm to find patterns across multiple cell divisions with high accuracy.We found that it is easy to evolve a system of enzymes that can maintain a particular chromatin state roughly stable, even without explicit boundary elements separating differentially modified chromatin domains. However, the success of this task depends on several previously unanticipated factors, such as the length of the initial state, the specific pattern that should be maintained, the time between replications, and chemical parameters such as enzymatic binding and dissociation rates. All these factors also influence the accumulation of errors in the wake of cell divisions.

Shaping epigenetic memory via genomic bookmarking

“…For example, acetyl groups on histones have half-lives <10 min ( 17 , 19 ), methyl groups on histones change during the period of one cell cycle ( 17 , 20 , 21 ) and DNA methylation is modified during development ( 16 ). The turnover may originate from histone replacement/displacement during transcription ( 7 , 17 , 22 , 23 ), replication ( 7 , 18 , 24 ) or from stochastic PTM deposition and removal ( 25 – 27 ).…”

Targeting histones for degradation in cancer cells as a novel strategy in cancer treatment

“…Moreover, addition of MMS reduced the levels of p21, suggesting that cell cycle arrest is probably not a primary mechanism for the joint treatment of TSA and MMS. Given that loss of the core histones can be critical to genome stability, transcriptional accuracy, DNA repair process, senescence, and survival (Altaf et al, 2007;Arnold et al, 2013;Dahlin et al, 2015;Dovey et al, 2013), our results reveal the induction of histone degradation as a new mechanism underlying the effect of these joint treatments against cancer cells. Thus, we propose that targeting the core histones for degradation could be a novel approach for the development of cancer therapy.…”

“…Together with the surrounding DNA, the core histones form the basic unit of the chromatin, the nucleosome, which contains an octamer of H2A, H2B, H3 and H4. The homeostasis of histones, histone modifications and histone-modifying enzymes is critical to genome stability, transcriptional accuracy, DNA repair process, senescence, and survival (Altaf et al, 2007;Arnold et al, 2013;Dahlin et al, 2015;Dovey et al, 2013). Among various histone modifications, histone acetylation associates with actively transcribed chromatin domains and the relaxed chromatin following DNA double-strand breaks (Campos and Reinberg, 2009;Downs et al, 2004;Murr et al, 2006;Reinke and Hörz, 2003).…”

Shaping Epigenetic Memory via Genomic Bookmarking: Supplementary Information

“…For example, acetyl groups on histones have half-lives < 10 minutes [17,19], methyl groups on histones change during the period of one cell cycle [17,20,21] and DNA methylation is modified during development [16]. The turnover may originate from histone replacement/displacement during transcription [7,17,22,23], replication [7,18,24] or from stochastic PTM deposition and removal [25][26][27].…”