Reciprocal H3.3 gene editing identifies K27M and G34R mechanisms in pediatric glioma including NOTCH signaling

Chen, Kuang-Yui Michael; Bush, Kelly; Klein, Rachel Herndon; Cervantes, Vanessa; Lewis, Nichole; Naqvi, Aasim; Carcaboso, Ángel M.; Lechpammer, Mirna; Knoepfler, Paul S.

doi:10.1038/s42003-020-1076-0

Cited by 36 publications

(56 citation statements)

References 49 publications

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“…61 H3K27M leads to rewiring of the H3K27me3 landscape in cells, causing tumor development, particularly gliomas. [63][64][65][66][67] Surprisingly, despite local inhibition of H3K27me3 due to H3K27M, several loci, including tumorsuppressor genes, show increased H3K27me3 enrichment in pediatric gliomas. EZH2 has already been shown to be a potential therapeutic target in these instances.…”

Section: Polycomb Repressive Complex 2 and Cancermentioning

confidence: 99%

Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

et al. 2021

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Genetic mutations or regulatory failures underlie cellular malfunction in many diseases, including colorectal cancer and inflammatory bowel diseases. However, mutational defects alone fail to explain the complexity of such disorders. Epigenetic regulation-control of gene action through chemical and structural changes of chromatin-provides a platform to integrate multiple extracellular inputs and prepares the cellular genome for appropriate gene expression responses. Coregulation by polycomb repressive complex 2-mediated trimethylation of lysine 27 on histone 3 and DNA methylation has emerged as one of the most influential epigenetic controls in colorectal cancer and many other diseases, but molecular details remain inadequate. Here we review the molecular interplay of these epigenetic features in relation to gastrointestinal development, homeostasis, and disease biology. We discuss other epigenetic mechanisms pertinent to the balance of trimethylation of lysine 27 on histone 3 and DNA methylation and their actions in gastrointestinal cancers. We also review the current molecular understanding of chromatin control in the pathogenesis of inflammatory bowel diseases.

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Section: Polycomb Repressive Complex 2 and Cancermentioning

confidence: 99%

Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

et al. 2021

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“…xenograft models [49,51,62]. H3K36M-mutant cells present inverse effects than H3K27M on the epigenetic landscape.…”

Section: Accepted Articlementioning

confidence: 99%

Oncohistones: a roadmap to stalled development

et al. 2021

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Since the discovery of recurrent mutations in histone H3 variants in pediatric brain tumours, so-called 'oncohistones' have been identified in various cancers. While their mechanism of action remains under active investigation, several studies have shed light on how they promote genome-wide epigenetic perturbations. These findings converge on altered post-translational modifications on two key lysine (K) residues of the H3 tail, K27 and K36, which regulate several cellular processes, including those linked to cell differentiation during development. We will review how these oncohistones affect the methylation of cognate residues, but also disrupt the distribution of opposing chromatin marks, creating genome-wide epigenetic changes which participate in the oncogenic process. Ultimately, tumorigenesis is promoted through the maintenance of a progenitor state at the expense of differentiation in defined cellular and developmental contexts. As these epigenetic disruptions are reversible, improved understanding of oncohistone pathogenicity can result in needed alternative therapies. Accepted ArticleThis article is protected by copyright. All rights reserved A number of cancers carry recurrent, somatic, gain-of-function, heterozygous mutations in different histone 3 (H3)-encoding genes, which lead to amino acid substitutions on key residues of the H3 tail. These hotspot H3 mutations, oncohistones as we label them, were first identified in a deadly brain cancer, pediatric high-grade gliomas (pHGGs), where they account for a large proportion of these tumours. Notably, they show remarkable spatio-temporal specificity, indicating that their pathogenesis may be closely linked to aberrant development [1,2]. Indeed, HGGs of the central nervous system midline (which includes the pons, thalamus and spine) target younger children, and show a high frequency (~80%) of H3 lysine to methionine, or rarely to isoleucine, substitutions (K27M/I). These K27M/I mutations occur in either canonical H3.1/H3.2 variants mainly in the pons, or in the non-canonical H3.3 variant across all brain midline structures (Figure 1) [2][3][4][5][6]. By contrast, in HGGs of the brain hemispheres, glycine 34 to arginine or valine (G34R/V) substitutions are specific to H3F3A, which encodes the H3.3 variant, and target primarily the temporo-parietal cortex in adolescents and young adults, where they account for ~30% of these tumours [2][3][4][5][6]. Other hemispheric H3 wild-type gliomas of adolescents and young adults (mean age of 33 years) occur primarily in fronto-parietal lobes and carry non-overlapping truncating mutations in SETD2 [7], the only H3K36 tri-methyltransferase in humans, and/or hotspot somatic mutations in isocitrate dehydrogenases 1/2 (IDH1/2) [3,6,[8][9][10]. IDH mutations generate a neomorphic enzyme and excess production of the oncometabolite 2-hydroxyglutarate, which competitively inhibits histone and DNA demethylases to affect the methylation of K residues on the H3 tail and promote a CpG island methylator phenotype (CIMP). Together, ...

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“…The function of K27M and G34R/W H3.3 mutations have been further investigated in disease-relevant systems using knockdown approaches (K27M knockdown in a xenografted tumor; G34W knockdown in primary tumor tissue) and CRISPR-mediated knock-in (isogenic reverting K27M and G34R to K27 and G34, respectively) [ 108 , 109 , 110 , 111 ]. Disease-relevant systems also include cancer mouse models expressing H3.3K27M in neuronal stem cells [ 102 , 112 ] and in vitro derived human neuronal progenitor cells (NPCs), in which a K27M or wild-type H3.3 was exogenously expressed together with other oncogenes observed in H3.3K27M mutant cancer cells [ 113 ].…”

Section: H33 Mutations In Cancermentioning

confidence: 99%

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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Reciprocal H3.3 gene editing identifies K27M and G34R mechanisms in pediatric glioma including NOTCH signaling

Cited by 36 publications

References 49 publications

Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

Oncohistones: a roadmap to stalled development

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

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