Oncogenic Mechanisms of Histone H3 Mutations

Weinberg, Daniel N.; Allis, C. David; Lü, Chao

doi:10.1101/cshperspect.a026443

Cited by 61 publications

(49 citation statements)

References 74 publications

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“…Notably, these mutations occur at, or near, two key lysine residues (K27 and K36) involved in chromatin regulation and collectively, these and other histone mutations found in cancer are referred to as "oncohistones." [2] The K27M mutation on H3.3 induces a dramatic loss of trimethylation at Lys27 (H3K27me3) and global reprogramming of regulatory histone modifications in pediatric brain cancers [3]. Interestingly, this study showed that although the H3.3K27M oncohistone comprised only a small fraction of the total H3 in cells, it mediated loss of global H3K27me3 in a dominant negative manner, depleting this mark from the majority of endogenous H3.…”

Section: Introductionmentioning

confidence: 81%

Characterization of H3.3K36M as a tool to study H3K36 methylation in cancer cells

Sankaran

Gozani

2017

Epigenetics

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Recurrent mutations at key lysine residues in the histone variant H3.3 are thought to play an etiologic role in the development of distinct subsets of pediatric gliomas and bone and cartilage cancers. H3.3K36M is one such mutation that was originally identified in chondroblastomas, and its expression in these tumors contributes to oncogenic reprogramming by triggering global depletion of dimethylation and trimethylation at H3K36 with a concomitant increase in the levels of H3K27 trimethylation. H3.3K36M expression can also cause epigenomic changes in cell types beyond chondrocytic cells. Here we show that expression of H3.3K36M in HT1080 fibrosarcoma cancer cells severely impairs cellular proliferation, which contrasts its role in promoting transformation of chondrocytic cells. H3.3K36M-associated cellular toxicity phenocopies the specific depletion of H3K36me2, but not loss of H3K36me3. We further find that the H3K36me2-associated toxicity is largely independent of changes in H3K27me3. Together, our findings lend support to the argument that H3K36me2 has distinct roles in cancer cells independent of H3K36me3 and H3K27me3, and highlight the use of H3.3K36M as an epigenetic tool to study H3K36 and H3K27 methylation dynamics in diverse cell types.

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Section: Introductionmentioning

confidence: 81%

Characterization of H3.3K36M as a tool to study H3K36 methylation in cancer cells

Sankaran

Gozani

2017

Epigenetics

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“…The multiple gene copies in these clustered arrays are sometimes confusingly referred to as "allelic" and the resulting combined protein isoforms are often considered to be "wild type" although both genes and protein products display variation in primary sequence and relative abundance, and their functional equivalence has not been tested. A number of mutations in individual canonical and variant histone genes have been revealed to contribute to cancer [12,21]. These "oncohistones" demonstrate that single amino acid changes in individual histone genes can have functional implications.…”

Section: Genomic Perspectivementioning

confidence: 99%

The human canonical core histone catalogue

Pinto

Flaus

2019

Preprint

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Core histone proteins H2A, H2B, H3, and H4 are encoded by a large family of genes distributed across the human genome. Canonical core histones contribute the majority of proteins to bulk chromatin packaging, and are encoded in 4 clusters by 65 coding genes comprising 17 for H2A, 18 for H2B, 15 for H3, and 15 for H4, along with at least 17 total pseudogenes. The canonical core histone genes display coding variation that gives rise to 11 H2A, 15 H2B, 4 H3, and 2 H4 unique protein isoforms. Although histone proteins are highly conserved overall, these isoforms represent a surprising and seldom recognised variation with amino acid identity as low as 77 % between canonical histone proteins of the same type. The gene sequence and protein isoform diversity also exceeds commonly used subtype designations such as H2A.1 and H3.1, and exists in parallel with the well-known specialisation of variant histone proteins. RNA sequencing of histone transcripts shows evidence for differential expression of histone genes but the functional significance of this variation has not yet been investigated. To assist understanding of the implications of histone gene and protein diversity we have catalogued the entire human canonical core histone gene and protein complement. In order to organise this information in a robust, accessible, and accurate form, we applied software build automation tools to dynamically generate the canonical core histone repertoire based on current genome annotations and then to organise the information into a manuscript format. Automatically generated values are shown with a light grey background. Alongside recognition of the encoded protein diversity, this has led to multiple corrections to human histone annotations, reflecting the flux of the human genome as it is updated and enriched in reference databases. This dynamic manuscript approach is inspired by the aims of reproducible research and can be readily adapted to other gene families.

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“…Recent high-throughput sequencing studies have identified specific recurrent mutations in histone proteins in a number of human neoplasms. 74 The consequences of these mutations have been studied in several cases, and they appear to globally alter the deposition of histone post-translational modifications, leading to changes in gene expression. For example, diffuse intrinsic pontine glioma is characterized by recurrent H3K27M mutations in H3.3, a histone H3 variant.…”

Section: Mutations In the Histones Themselves: Giant Cell Tumor Of Bomentioning

confidence: 99%

Epigenetic Alterations in Bone and Soft Tissue Tumors

Wojcik

Cooper²

2017

Advances in Anatomic Pathology

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Human malignancies are driven by heritable alterations that lead to unchecked cellular proliferation, invasive growth and distant spread. Heritable changes can arise from changes in DNA sequence, or, alternatively, through altered gene expression rooted in epigenetic mechanisms. In recent years, high-throughput sequencing of tumor genomes has revealed a central role for mutations in epigenetic regulatory complexes in oncogenic processes.1–3 Through interactions with or direct modifications of chromatin, these proteins help control the accessibility of genes, and thus the transcriptional profile of a cell. Dysfunction in these proteins can lead to activation of oncogenic pathways or silencing of tumor suppressors. While epigenetic regulators are altered across a broad spectrum of human malignancies, they play a particularly central role in tumors of mesenchymal and neuroectodermal origin (table 1). This review will focus on recent advances in the understanding of the molecular pathogenesis of a subset of tumors in which alterations in the polycomb family of chromatin modifying complexes, the SWI/SNF family of nucleosome remodelers, and histones play a central role in disease pathogenesis. While this review will focus predominantly on the molecular mechanisms underlying these tumors, each section will also highlight areas in which an understanding of the molecular pathogenesis of these diseases has led to the adoption of novel immunohistochemical and molecular markers.

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Oncogenic Mechanisms of Histone H3 Mutations

Cited by 61 publications

References 74 publications

Characterization of H3.3K36M as a tool to study H3K36 methylation in cancer cells

Characterization of H3.3K36M as a tool to study H3K36 methylation in cancer cells

The human canonical core histone catalogue

Epigenetic Alterations in Bone and Soft Tissue Tumors

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