DNA methylation cues in nucleosome geometry, stability and unwrapping

Abstract

Cytosine methylation at the 5-carbon position is an essential DNA epigenetic mark in many eukaryotic organisms. Although countless structural and functional studies of cytosine methylation have been reported, our understanding of how it influences the nucleosome assembly, structure, and dynamics remains obscure. Here, we investigate the effects of cytosine methylation at CpG sites on nucleosome dynamics and stability. By applying long molecular dynamics simulations on several microsecond time scale, we generate extensive atomistic conformational ensembles of full nucleosomes. Our results reveal that methylation induces pronounced changes in geometry for both linker and nucleosomal DNA, leading to a more curved, under-twisted DNA, narrowing the adjacent minor grooves, and shifting the population equilibrium of sugar-phosphate backbone geometry. These DNA conformational changes are associated with a considerable enhancement of interactions between methylated DNA and the histone octamer, doubling the number of contacts at some key arginines. H2A and H3 tails play important roles in these interactions, especially for DNA methylated nucleosomes. This, in turn, prevents a spontaneous DNA unwrapping of 3–4 helical turns for the methylated nucleosome with truncated histone tails, otherwise observed in the unmethylated system on several microseconds time scale.

Phase Separation and Correlated Motions in Motorized Genome

“…Euchromatin and heterochromatin are known to exhibit distinct chemical modifications − and interact with different regulatory proteins , and nuclear bodies. ,− The chemical modifications themselves could drive chromatin demixing by altering nucleosome interactions. For example, acetylation could neutralize the positive charges on histone tails to weaken their binding with DNA, − while methylation may lead to undertwisted DNA that strengthens its interactions with histones. , It is conceivable that nucleosomes with similar histone marks share more favorable interactions, driving their separation from other differentially modified ones. On the other hand, chromatin regulators associated with specific histone marks often contain intrinsically disordered regions that exhibit multivalent interactions to undergo liquid–liquid phase separation themselves. − These proteins may further contribute to the compartmentalization of various chromatin types.…”

“…For example, acetylation could neutralize the positive charges on histone tails to weaken their binding with DNA, 34−37 while methylation may lead to undertwisted DNA that strengthens its interactions with histones. 38,39 It is conceivable that nucleosomes with similar histone marks share more favorable interactions, driving their separation from other differentially modified ones. On the other hand, chromatin regulators associated with specific histone marks often contain intrinsically disordered regions that exhibit multivalent interactions to undergo liquid−liquid phase separation themselves.…”

Breaking the aging epigenetic barrier

“…DNA damage also increase histone degradation ( Hauer and Gasser, 2017 ) and histone tail cleavage has been associated with various cellular processes ( Yi and Kim 2018 ). All-atom computational modeling shows that histone tail dynamics modulate the DNA accessibility ( Armeev et al, 2021 ; Peng et al, 2021 ) and DNA methylation leads to more curved under-twisted DNA ( Li et al, 2022 ). Taking these factors into account, one might predict dramatic differences between the biophysical properties of aged chromatin versus young chromatin.…”

Histone variant H2A.Z modulates nucleosome dynamics to promote DNA accessibility

“…1d ). Previous microsecond-long simulations and quantitative modeling showed that canonical nucleosomes exhibited spontaneous DNA unwrapping for systems without histone tails 32 – 34 . The roles of histone tails in DNA unwrapping will be discussed in the next sections.…”