Histone H3.3 phosphorylation amplifies stimulation-induced transcription

Armache, Anja; Yang, Shuang; Paz, Alexia Martínez de; Robbins, Lexi; Durmaz, Ceyda; Cheong, Jin-Gyu; Ravishankar, Arjun; Daman, Andrew W; Ahimovic, Dughan J.; Klevorn, Thaís; Yue, Yuan; Arslan, Tanja; Lin, Shu; Panchenko, Tanya; Hrit, Joel; Wang, Miao; Thudium, Samuel; Garcia, Benjamin A.; Korb, Erica; Armache, Karim‐Jean; Rothbart, Scott B.; Hake, Sandra B.; Allis, C. David; Li, Haitao; Josefowicz, Steven Z.

doi:10.1038/s41586-020-2533-0

Cited by 101 publications

(96 citation statements)

References 75 publications

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“…In the nucleus, IKKα is recruited to the NF-κB transcription complex to phosphorylate multiple substrates, such as histone H3 at Ser10 49,50 , CBP at Ser1382/1386 69 , p65 at Ser536 93 , and SMRT at Ser2410 94 , to promote NF-κB-dependent gene transcription. A recent research showed that IKKα phosphorylated histone H3.3 at Ser31 to amplify stimulation-induced transcription 95 . Although we only demonstrated histone H3 as a substrate of IKKα in this study, we cannot exclude the possibility that IKKα phosphorylates other substrates.…”

Section: Discussionmentioning

confidence: 99%

Targeting HECTD3-IKKα axis inhibits inflammation-related metastasis

Chen¹,

Li²,

Liang³

et al. 2021

Preprint

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Metastasis is the leading cause of cancer-related death. Surgery is a common intervention for most primary solid tumors; however, surgical trauma-related systemic inflammation facilitates distant tumor metastasis by increasing the spread and adhesion of tumor cells to vascular endothelial cells. Currently, there are no effective interventions to prevent distant metastasis. Here, we show that HECTD3 deficiency in vascular endothelial cells (ECs) significantly reduces tumor metastasis in tumor resection metastasis, LPS-induced metastasis and MMTV-Neu metastasis models. HECTD3 depletion downregulates expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, in mouse primary ECs and in human primary umbilical vein ECs stimulated by inflammatory factors and inhibits adhesion of tumor cells to ECs both in vitro and in vivo. We demonstrate that HECTD3 promotes stabilization and kinase activity of IKKα by ubiquitinating IKKα with K27- and K63-linked polyubiquitin chains at K296, increasing phosphorylation of histone H3 at Ser10 to promote NF-κB target gene transcription. IKKα kinase inhibitors prevented LPS-induced pulmonary metastasis. These findings reveal the promotional role of the HECTD3-IKKα axis in tumor hematogenous metastasis and provide a potential strategy for tumor metastasis prevention.

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Section: Discussionmentioning

confidence: 99%

Targeting HECTD3-IKKα axis inhibits inflammation-related metastasis

Chen¹,

Li²,

Liang³

et al. 2021

Preprint

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“…This observation could be explained by several mechanisms, for example: (i) H3.3S31ph may recruit a p300 activator or prevent the binding of an inhibitor at enhancers; (ii) H3.3S31ph allosterically stimulates p300 activity, possibly by forming a stable interaction in a manner analogous to stimulation by eRNA (although the negative charge provided by H3.3S31ph is much less than that of an eRNA, and to date, there is no structural evidence of stable interaction between p300 and the H3 tail [ 168 ]); or (iii) phosphorylated H3.3 may be a more permissive substrate which, upon acetylation, allows p300 to remain chromatin-bound via its bromodomain to acetylate adjacent canonical histones. Interestingly, H3.3S31ph has previously been linked to gene activation [ 169 ] and another recent study reported structural evidence that H3.3S31ph promotes the histone methyltransferase activity of SETD2 towards H3K36 during macrophage stimulation [ 170 ]. Taken together, these findings suggest that one function of the highly conserved serine at position 31 on H3.3 is to influence chromatin states at active regulatory elements and genes.…”

Section: Mechanisms Of Cbp/p300 Activationmentioning

confidence: 99%

Establishment and function of chromatin modification at enhancers

Tafessu

Banaszynski

2020

Open Biol.

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How a single genome can give rise to distinct cell types remains a fundamental question in biology. Mammals are able to specify and maintain hundreds of cell fates by selectively activating unique subsets of their genome. This is achieved, in part, by enhancers—genetic elements that can increase transcription of both nearby and distal genes. Enhancers can be identified by their unique chromatin signature, including transcription factor binding and the enrichment of specific histone post-translational modifications, histone variants, and chromatin-associated cofactors. How each of these chromatin features contributes to enhancer function remains an area of intense study. In this review, we provide an overview of enhancer-associated chromatin states, and the proteins and enzymes involved in their establishment. We discuss recent insights into the effects of the enhancer chromatin state on ongoing transcription versus their role in the establishment of new transcription programmes, such as those that occur developmentally. Finally, we highlight the role of enhancer chromatin in new conceptual advances in gene regulation such as condensate formation.

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“…By systematically mutating H3.3 residues, the authors found that H3.3 serine 31 is essential for Xenopus gastrulation, and—using phosphomimetic mutants—they also linked serine 31 phosphorylation to H3K27ac [ 142 ]. In another study, Armache et al, 2020 investigated the role of H3.3S31ph in lipopolysaccharide-induced transcription in macrophages [ 143 ]. They found that H3.3 serine 31 phosphomimetic mutants and H3.3S31ph recruit SETD2 in order to drive rapid stimulus-induced gene expression [ 143 ].…”

Section: H33 Mutagenesis Beyond Cancermentioning

confidence: 99%

“…In another study, Armache et al, 2020 investigated the role of H3.3S31ph in lipopolysaccharide-induced transcription in macrophages [ 143 ]. They found that H3.3 serine 31 phosphomimetic mutants and H3.3S31ph recruit SETD2 in order to drive rapid stimulus-induced gene expression [ 143 ].…”

Section: H33 Mutagenesis Beyond Cancermentioning

confidence: 99%

“…The histone variant H3.3 accounts for a relatively small portion of the total H3 pool in dividing cells (e.g., ~20% of the total H3 in mESCs [ 28 ]). However, single amino acid substitutions of H3.3 exhibit major impacts on gene expression, the cell cycle, cell differentiation, cellular homeostasis, and organism development [ 126 , 127 , 141 , 142 , 143 , 146 ]. This could be, in part, due to the tightly regulated deposition of H3.3 at specific genomic regions such as promoters, enhancers, and several repeat elements [ 39 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Histone Variant H3.3 Mutations in Defining the Chromatin Function in Mammals

Trovato

Patil

Gehre

et al. 2020

Cells

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The systematic mutation of histone 3 (H3) genes in model organisms has proven to be a valuable tool to distinguish the functional role of histone residues. No system exists in mammalian cells to directly manipulate canonical histone H3 due to a large number of clustered and multi-loci histone genes. Over the years, oncogenic histone mutations in a subset of H3 have been identified in humans, and have advanced our understanding of the function of histone residues in health and disease. The oncogenic mutations are often found in one allele of the histone variant H3.3 genes, but they prompt severe changes in the epigenetic landscape of cells, and contribute to cancer development. Therefore, mutation approaches using H3.3 genes could be relevant to the determination of the functional role of histone residues in mammalian development without the replacement of canonical H3 genes. In this review, we describe the key findings from the H3 mutation studies in model organisms wherein the genetic replacement of canonical H3 is possible. We then turn our attention to H3.3 mutations in human cancers, and discuss H3.3 substitutions in the N-terminus, which were generated in order to explore the specific residue or associated post-translational modification.

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Histone H3.3 phosphorylation amplifies stimulation-induced transcription

Cited by 101 publications

References 75 publications

Targeting HECTD3-IKKα axis inhibits inflammation-related metastasis

Targeting HECTD3-IKKα axis inhibits inflammation-related metastasis

Establishment and function of chromatin modification at enhancers

Histone Variant H3.3 Mutations in Defining the Chromatin Function in Mammals

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