A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer

Morgan, Marc A.; Popova, Irina K; Vaidya, Anup; Burg, Jonathan M.; Marunde, Matthew R.; Rendleman, Emily J.; Dumar, Zachary J.; Watson, Rachel; Meiners, Matthew J.; Howard, Sarah A.; Khalatyan, Natalia; Vaughan, Robert M.; Rothbart, Scott B.; Keogh, Michael-C.; Shilatifard, Ali

doi:10.1101/gad.348766.121

Cited by 24 publications

(35 citation statements)

References 68 publications

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“…When moving from the peptide to Nuc context we (and others) consistently observe individual reader domains to show reduced affinity and restricted specificity 23–26,35,51 . An exception to this is readers with intrinsic DNA binding ability, such as the PWWPs.…”

Section: Discussionsupporting

confidence: 72%

“…6b , c ). Thus, H4 tail accessibility is reader dependent (as also recently demonstrated for PHIP BD1-BD2 51 ), and the ability to bind may rely on several factors including overall affinity or different engagement mechanisms. For instance, BRD4 BD1 (unlike BPTF BD) can associate with DNA 52 , and such competition may help disengage the H4 tail from the nucleosome core.…”

Section: Bptf Phd-bd Demonstrates Restricted Specificity and Synergis...mentioning

confidence: 72%

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Nucleosome conformation dictates the histone code

Marunde

Fuchs

Burg

et al. 2022

Preprint

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Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized "codes" that are read by specialized regions (reader domains) in chromatin associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP-histone PTM] specificity, and thus decipher the histone code / guide epigenetic therapies. However, this has largely been done using a reductive approach of isolated reader domains and histone peptides, with the assumption that PTM readout is unaffected by any higher order factors. Here we show that CAP-histone PTM interaction is in fact dependent on nucleosome context. Our results indicate this is due to histone tail accessibility and the associated impact on binding potential of reader domains. We further demonstrate that the in vitro specificity of a tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. This necessitates we refine the "histone code" concept and interrogate it at the nucleosome level.

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Section: Discussionsupporting

confidence: 72%

Section: Bptf Phd-bd Demonstrates Restricted Specificity and Synergis...mentioning

confidence: 72%

Nucleosome conformation dictates the histone code

Marunde

Fuchs

Burg

et al. 2022

Preprint

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“…A continued observation from this study is that the binding preference of readers (in this case PHD-fingers that engage histone H3K4) are narrowed on nucleosomes relative to histone peptides (Figure 1 & S1) (Marunde et al, 2022a;Morgan et al, 2021). This difference in binding further highlights the importance of using nucleosomes as physiologically relevant substrates for in vitro interaction assays.…”

Section: Discussionmentioning

confidence: 58%

“…How histone readers engage nucleosomes is an extensively researched area of chromatin biology. Most investigators have used PTM-defined histone peptides to characterize reader binding, although these often display a refined preference to similarly modified nucleosomes (Marunde et al, 2022b(Marunde et al, , 2022aMorgan et al, 2021;Morrison et al, 2018). To further assess this potential, we used the dCypher ® approach (Jain et al, 2020;Marunde et al, 2022b;Morgan et al, 2021;Weinberg et al, 2021) to measure the interactions of three PHD readers (from KDM7A, DIDO1, and MLL5: the queries) with PTM-defined peptides and nucleosomes (the potential targets).…”

Section: Phd Finger Readers Show Narrowed Selectivity For Histone Tai...mentioning

confidence: 99%

An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability

Jain

Marunde

Burg

et al. 2022

Preprint

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In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The DNA-bound state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation (K9ac, K14ac, K18ac) is linked to increased engagement of H3K4me3 by the BPTF PHD finger, but it is unknown if this mechanism has broader extension. Here we show that cis H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and further extends to H3K4 writers, notably methyltransferase MLL1. This regulation is nucleosome-dependent and also observed in vivo, where H3 acetylation correlates with increased levels of cis H3K4me. These observations reveal an acetylation "chromatin switch" on the H3 N-terminal tail that modulates the accessibility and function of H3K4 methylation in chromatin. Our findings also resolve the long-standing question of why H3K4me3 levels are linked with H3 acetylation.

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“…Furthermore, loss-of-function variants in CUL4B are also associated with overlapping symptoms of intellectual disability (Tarpey et al 2007) implicating a critical role of the CRL4 DCAF14 complex in genome maintenance. In this light, a recent study highlights DCAF14 mediated trivalent nucleosome recognition for CRL4 recruitment to chromatin for gene expression (Morgan et al 2021) and further demonstrates the significance of DCAF14 in regulating several chromatin-related processes.…”

Section: Discussionmentioning

confidence: 92%

PHIP variants associated with Chung–Jansen syndrome disrupt replication fork stability and genome integrity

Tirado-Class

Hathaway

Chung

et al. 2022

Cold Spring Harb Mol Case Stud

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Chung-Jansen syndrome (CJS) is a rare, autosomal dominant disorder characterized by developmental delay, intellectual disability/cognitive impairment, behavioral challenges, obesity, and dysmorphic features. CJS is associated with heterozygous variants in PHIP (Pleckstrin-Homology Interacting Protein), a gene that encodes one of several substrate receptors for Cullin4-RING (CRL4) E3 ubiquitin ligase complex. Full length PHIP, also called DCAF14, was recently identified to function as a replication stress response protein. Herein, we report the identification of two PHIP missense variants identified by exome sequencing in unrelated individuals with CJS. The variants p.D488V and p.E963G occur in different functional elements of DCAF14- WD40 repeat domain and pleckstrin homology-binding region (PBR), respectively. Using DNA fiber assays, we reveal that cells expressing either variant exhibit defective replication fork progression in conditions of replication stress. Furthermore, unlike wild type DCAF14, both variants fail to accomplish DNA replication after exposure to genotoxic stress indicating a critical role of DCAF14 in protecting stalled replication forks. Thus, we have identified replication defects associated with CJS variants and predict replication-associated genome instability with CJS syndrome.

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A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer

Cited by 24 publications

References 68 publications

Nucleosome conformation dictates the histone code

Nucleosome conformation dictates the histone code

An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability

PHIP variants associated with Chung–Jansen syndrome disrupt replication fork stability and genome integrity

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