Nucleosomal Asymmetry Shapes Histone Mark Binding and Promotes Poising at Bivalent Domains

Bryan, Elana; Warburton, Marie; Km, Webb; McLaughlin, Katie A.; Spanos, Christos; Ambrosi, Christina M.; Major, Ian; Baubec, Tuncay; Rappsilber, Juri; Voigt, Philipp

doi:10.1101/2021.02.08.430127

Cited by 3 publications

(1 citation statement)

References 80 publications

(111 reference statements)

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“…Native chemical ligation was performed essentially as described (Bartke et al , 2010; Bryan et al , 2021), with some modifications. Peptides corresponding to human H3.1 residues 1-43 containing H3K36me2 and H3K27me2K36me2 with C-terminal thioesters were synthesised by Peptide Synthetics.…”

Section: Methodsmentioning

confidence: 99%

The N-terminal region of DNMT3A combines multiple chromatin reading motifs to guide recruitment

Wapenaar,

Clifford,

Rolls

et al. 2023

Preprint

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DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns. However, the mechanisms underlying DNMT3A recruitment to and function within different chromatin environments remain unclear. Using a combination of biochemical and structural approaches we find that DNMT3A interacts using multiple interfaces with chromatin; directly binding generic nucleosome features as well as site-specific post-translational histone modifications. The N-terminal region, unique to the DNMT3A1 isoform, is essential for these interactions and stabilises H3K36me2-nucleosome recruitment. Intriguingly, in the same region critical for nucleosome binding we also map a ubiquitylation-dependent recruitment motif (UDR). The UDR binds specifically to ubiquitylated H2AK119, explaining the previously observed recruitment to Polycomb-occupied heterochromatin. A cryo-EM structure of DNMT3A1-DNMT3L with a modified nucleosome reveals that the UDR interacts with the nucleosome surface including the acidic patch. Previously unexplained disease-associated mutations are present in the UDR and ablate nucleosome interactions. This leads to an increased understanding of how DNMT3A1 recruitment occurs in the genome and highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome.

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Section: Methodsmentioning

confidence: 99%

The N-terminal region of DNMT3A combines multiple chromatin reading motifs to guide recruitment

Wapenaar,

Clifford,

Rolls

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment

Wapenaar,

Clifford,

Rolls

et al. 2024

EMBO Rep

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DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Here we structurally and biochemically explore the interaction of DNMT3A1 with diverse modified nucleosomes indicative of different chromatin environments. A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex with a H2AK119ub nucleosome reveals that the DNMT3A1 ubiquitin-dependent recruitment (UDR) motif interacts specifically with H2AK119ub and makes extensive contacts with the core nucleosome histone surface. This interaction facilitates robust DNMT3A1 binding to nucleosomes, and previously unexplained DNMT3A disease-associated mutations disrupt this interface. Furthermore, the UDR-nucleosome interaction synergises with other DNMT3A chromatin reading elements in the absence of histone ubiquitylation. H2AK119ub does not stimulate DNMT3A DNA methylation activity, as observed for the previously described H3K36me2 mark, which may explain low levels of DNA methylation on H2AK119ub marked facultative heterochromatin. This study highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome surface and increases our understanding of how DNMT3A1 chromatin recruitment occurs.

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Nucleosomal asymmetry: a novel mechanism to regulate nucleosome function

Valsakumar,

Voigt

2024

Biochemical Society Transactions

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Nucleosomes constitute the fundamental building blocks of chromatin. They are comprised of DNA wrapped around a histone octamer formed of two copies each of the four core histones H2A, H2B, H3, and H4. Nucleosomal histones undergo a plethora of posttranslational modifications that regulate gene expression and other chromatin-templated processes by altering chromatin structure or by recruiting effector proteins. Given their symmetric arrangement, the sister histones within a nucleosome have commonly been considered to be equivalent and to carry the same modifications. However, it is now clear that nucleosomes can exhibit asymmetry, combining differentially modified sister histones or different variants of the same histone within a single nucleosome. Enabled by the development of novel tools that allow generating asymmetrically modified nucleosomes, recent biochemical and cell-based studies have begun to shed light on the origins and functional consequences of nucleosomal asymmetry. These studies indicate that nucleosomal asymmetry represents a novel regulatory mechanism in the establishment and functional readout of chromatin states. Asymmetry expands the combinatorial space available for setting up complex sets of histone marks at individual nucleosomes, regulating multivalent interactions with histone modifiers and readers. The resulting functional consequences of asymmetry regulate transcription, poising of developmental gene expression by bivalent chromatin, and the mechanisms by which oncohistones deregulate chromatin states in cancer. Here, we review recent progress and current challenges in uncovering the mechanisms and biological functions of nucleosomal asymmetry.

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Nucleosomal Asymmetry Shapes Histone Mark Binding and Promotes Poising at Bivalent Domains

Cited by 3 publications

References 80 publications

The N-terminal region of DNMT3A combines multiple chromatin reading motifs to guide recruitment

The N-terminal region of DNMT3A combines multiple chromatin reading motifs to guide recruitment

The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment

Nucleosomal asymmetry: a novel mechanism to regulate nucleosome function

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