Hybrid protein assembly-histone modification mechanism for PRC2-based epigenetic switching and memory

Lövkvist, Cecilia; Mikulski, Paweł; Reeck, Svenja; Hartley, Matthew; Dean, Caroline; Howard, Martin

doi:10.7554/elife.66454

Cited by 28 publications

(25 citation statements)

References 66 publications

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“…The analog autonomous pathway component of FLC regulation controls transcription through an FCA-mediated mechanism. Based on previous studies on the interplay between transcription and PRC2 silencing (Beltran, Yates et al 2016, Berry, Dean et al 2017, Holoch, Wassef et al 2021, Lövkvist, Mikulski et al 2021), we propose that digital Polycomb silencing is prevented by high transcription in fca-1 , while low transcription is not sufficient to significantly oppose silencing in Ler. In fca-3 , the dynamical antagonism between Polycomb silencing and an intermediate level of transcription is still ongoing at our experimentally accessible timepoints.…”

Section: Discussionmentioning

confidence: 88%

Integrating analog and digital modes of gene expression at Arabidopsis FLC

Antoniou-Kourounioti

Meschichi

Reeck

et al. 2022

Preprint

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Quantitative gene regulation at the cell population-level can be achieved by two fundamentally different modes of regulation at individual gene copies. A “digital” mode involves binary ON/OFF expression states, with population-level variation arising from the proportion of gene copies in each state, while an “analog” mode involves graded expression levels at each gene copy. At the Arabidopsis floral repressor FLOWERING LOCUS C (FLC), “digital” Polycomb silencing is known to facilitate quantitative epigenetic memory in response to cold. However, whether FLC regulation before cold involves analog or digital modes is unknown. Using quantitative fluorescent imaging of FLC mRNA and protein, together with mathematical modelling, we find that FLC expression before cold is regulated by both analog and digital modes. We observe a temporal separation between the two modes, with analog preceding digital. The analog mode can maintain intermediate expression levels at individual FLC gene copies, before subsequent digital silencing, consistent with the copies switching OFF stochastically and heritably without cold. This switch leads to a slow reduction in FLC expression at the cell population-level. These data present a new paradigm for gradual repression, elucidating how analog transcriptional and digital epigenetic memory pathways can be integrated.

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Section: Discussionmentioning

confidence: 88%

Integrating analog and digital modes of gene expression at Arabidopsis FLC

Antoniou-Kourounioti

Meschichi

Reeck

et al. 2022

Preprint

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“…Finally, epigenetic inheritance in bistable epigenetic regions often requires silencers or other protein-based memory elements (8, 13, 43) in addition to positive feedback. Interestingly, a recent study in budding yeast by (8) showed that the degree of bistability depends on both the degree of nucleation at silencers and positive feedback via recruited nucleosome conversions.…”

Section: Resultsmentioning

confidence: 99%

Theoretical analysis of confinement mechanisms for epigenetic modifications of nucleosomes

Nickels¹,

Sneppen²

2022

Preprint

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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.

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“…This could be tested by observing the fate of artificial ectopic mark domains of different lengths [34, 53, 54]. Very small domains that appear to exhibit a cis -memory of silencing [55] may rely on alternative mechanisms [56].…”

Section: Discussionmentioning

confidence: 99%

Design principles of 3D epigenetic memory systems

Owen

Osmanović²,

Mirny

2022

Preprint

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The epigenetic state of a cell is associated with patterns of chemical modifications of histones ("marks") across the genome, with different marks typical of active (euchromatic) and inactive (heterochromatic) genomic regions. These mark patterns can be stable over many cell generations—a form of epigenetic memory—despite their constant erosion due to replication and other processes. Enzymes that place histone marks are often stimulated by the same marks, as if "spreading" marks between neighboring histones. But this positive feedback may not be sufficient for stable memory, raising the question of what is. In this work, we show how 3D genome organization—in particular, the compartmental segregation of euchromatin and heterochromatin—could serve to stabilize an epigenetic memory, as long as (1) there is a large density difference between the compartments, (2) the modifying enzymes can spread marks in 3D, and (3) the enzymes are limited in abundance relative to their histone substrates. We introduce a biophysical model stylizing chromatin and its dynamics through the cell cycle, in which enzymes spread self-attracting marks on a polymer. We find that marks localize sharply and stably to the denser compartment, but over several cell generations, the model generically exhibits uncontrolled spread or global loss of marks. Strikingly, imposing limitation of the modifying enzymes—a plausible but oft-neglected element—totally changes this picture, yielding an epigenetic memory system, stable for hundreds of cell generations. Our model predicts a rich phenomenology to compare to experiments, and reveals basic design principles of putative epigenetic memory systems relying on compartmentalized 3D genome structure for their function.

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Hybrid protein assembly-histone modification mechanism for PRC2-based epigenetic switching and memory

Cited by 28 publications

References 66 publications

Integrating analog and digital modes of gene expression at Arabidopsis FLC

Integrating analog and digital modes of gene expression at Arabidopsis FLC

Theoretical analysis of confinement mechanisms for epigenetic modifications of nucleosomes

Design principles of 3D epigenetic memory systems

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