Domain model explains propagation dynamics and stability of K27 and K36 methylation landscapes

Abstract

Chromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle and the principles governing heritability remain unclear. Here, we take a quantitative computational modeling approach to describes propagation of K27 and K36 methylation states. We measure combinatorial K27 and K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones. Using model comparison, we reject active global demethylation and invoke the existence of domains defined by distinct methylation endpoints. We find that K27me3 on pre-existing histones stimulates the rate of de novo K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed, quantitative picture of the mutual antagonism between K27 and K37 methylation, and propose that it stabilizes epigenetic states across cell division.

Collective regulation of chromatin modifications predicts replication timing during cell cycle

“…The contraction of H3K27me3 regions upon a genetic perturbation was accompanied by a coordinated expansion of neighboring H3K36me2 regions to the new H3K27me3 boundary (Figure S2B). Collectively, these data are consistent with previous observations documenting the exclusivity between combinations of these histone marks at the local and more global level (Alabert et al, 2020;Streubel et al, 2018;Weinberg et al, 2019;Yuan et al, 2011).…”

“…Our study demonstrates that at 50-kb resolution there are three distinct histone marks that are exclusive of one another across the genome (H3K9me3, H3K27me3, and H3K36me2), which is consistent with prior studies (Alabert et al, 2020;Streubel et al, 2018;Weinberg et al, 2019;Yuan et al, 2011). The corresponding chromatin states, along with the active state, were insulated from one another and maintained during cell cycle, while having distinct roles in local initiation, propagation, and completion of replication.…”

The histone chaperone FACT facilitates heterochromatin spreading by regulating histone turnover and H3K9 methylation states

“…Particularly low histone turnover may be important for enzymes with slow kinetic rates, like Clr4 that generates H3K9me3 roughly 10 times slower than H3K9me1 and H3K9me2 (Al-Sady et al, 2013). Similar slow kinetic properties are found for the human K9 and K27 methyltransferases, G9a (Patnaik et al, 2004) and EZH2 (Alabert et al, 2020;Chory et al, 2019), respectively. Thus, low histone turnover emerges as a critical factor for the establishment of repressive chromatin domains.…”

Antagonistic histone post-translational modifications improve the fidelity of epigenetic inheritance - a Bayesian perspective

“…the authors discuss how the antagonistic roles of the aforementioned modifications are necessary for the successful switching of epigenetic states in Arabidopsis for vernalization in winter. Their model and findings suggest a mutual antagonism between these modifications, similar to those in [31]. In [32], the authors propose that in HeLa cells, the nucleosomes containing H3K36me3 do not have the H3K27me3 except in newly synthesized H3.…”