Generalized nucleation and looping model for epigenetic memory of histone modifications

Abstract

Histone modifications can redistribute along the genome in a sequenceindependent manner, giving rise to chromatin position effects and epigenetic memory. The underlying mechanisms shape the endogenous chromatin landscape and determine its response to ectopically targeted histone modifiers. Here, we simulate linear and loopingdriven spreading of histone modifications and compare both models to recent experiments on histone methylation in fission yeast. We find that a generalized nucleation-and-looping mechanism describes key observations on engineered and endogenous methylation domains including intrinsic spatial confinement, independent regulation of domain size and memory, variegation in the absence of antagonists, and coexistence of short-and long-term memory at loci with weak and strong constitutive nucleation. These findings support a straightforward relationship between the biochemical properties of chromatin modifiers and the spatiotemporal modification pattern. The proposed mechanism gives rise to a phase diagram for cellular memory that may be generally applicable to explain epigenetic phenomena across different species.epigenetic memory | heterochromatin | epigenome editing | histone modification | stochastic simulation H istone posttranslational modifications regulate cellular processes including gene expression, DNA replication, and DNA repair (1, 2). Some of these modifications can spread along the genome independently of the underlying DNA sequence, forming extended domains of modified histones. Well-known examples are di/trimethylation of histone 3 at lysine 9 (H3K9me2/3) and at lysine 27 (H3K27me2/3), which are enriched in heterochromatin and play a role in gene silencing (3-5). H3K9me2/3 can spread around centromeres (6) and telomeres (7), and H3K27me2/3 can spread around dedicated response elements within the genome (8, 9), causing socalled chromatin position effects by repressing genes within the methylated domains (7, 10, 11). The enzymes that are responsible for heterochromatic H3K9me2/3 are Clr4 in fission yeast and Suv39h in metazoans, and the PRC2 complex catalyzes H3K27me2/3 (12). By stably tethering these enzymes to chromatin, extended engineered domains enriched for the respective modification can be formed (13)(14)(15)(16)(17)(18)(19)(20). Furthermore, both modifications can confer epigenetic memory at least across several cell divisions (14)(15)(16)(17)21).Aberrations in histone modification patterns and the responsible enzymes are involved in several diseases, including cancer (22, 23). It has recently become possible to recruit histone-modifying enzymes to endogenous target sites, e.g., by using the CRISPR-Cas9 system, thereby eliciting programmed changes to histone modifications and triggering specific position effects (24,25). Due to the functional relevance of the chromatin landscape, this technique holds promise for future clinical applications (26,27). Therefore, it is particularly important to understand if and how far modifications can spread and how long engineered domains a...

How Communication Between Nucleosomes Enables Spreading and Epigenetic Memory of Histone Modifications

“…In most spreading models, domain formation is triggered by local nucleation at a particular genomic locus or nucleosome (Figure A, left) . The size and shape of the resulting domains can readily be compared to the experimentally observed profiles around known nucleation sites.…”

“…Different mechanisms have been used to describe how nucleosomes talk to each other to couple their states. Some models are based on looping‐driven information exchange (Figure B, left), which is governed by the distance‐dependent contact probability between nucleosomes discussed above . Others consider uniform long‐range interactions within a domain of interest, which means that nucleosomes can exchange information with each other independently of the genomic distance between them .…”

PRC2 bridges non-adjacent nucleosomes to establish heterochromatin

“…Instead, PRC2 possesses the inherent ability to bypass spacer nucleosomes and perhaps other roadblocks when carrying out the read-andwrite function. This feature is required to explain several epigenetic phenomena observed in the cell such as memory and bistability as illustrated by prior theoretical studies (31,32). Such a looping mechanism may be applicable to other chromatin-modifying enzymes, providing flexibility and robustness for their operation (33).…”

Recent advances in computational epigenetics

“…The formulation of models to explain the biological processes, together with interrogation of diverse data sources and in-depth integrated analysis, is an essential feature of the new paradigm. [40][41][42][43][44] In the following sections, modeling epigenetic dynamics from DNA methylation to histone modifications is considered, with achievements and challenges being discussed. The computational resources employed to manage various available data-types are considered, and technology-dependent methods and tools to produce quantitative epigenetic data are discussed next.…”

“…Cross talk between DNA methylation pathways and histone modifications has also been considered, 20 as have multi-scale effects in a generalized nucleation and looping model for epigenetic memory of histone modifications. 44 Cell mechanisms, producing and sustaining these patterns, were investigated as a prerequisite for predicting efficacy of epigenetic drug therapy.…”