Histone H3 mutations--a special role for H3.3 in tumorigenesis? - PubMed (original) (raw)

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Histone H3 mutations--a special role for H3.3 in tumorigenesis?

Satish Kallappagoudar et al. Chromosoma. 2015 Jun.

Abstract

Brain tumors are the most common solid tumors in children. Pediatric high-grade glioma (HGG) accounts for ∼8-12 % of these brain tumors and is a devastating disease as 70-90 % of patients die within 2 years of diagnosis. The failure to advance therapy for these children over the last 30 years is largely due to limited knowledge of the molecular basis for these tumors and a lack of disease models. Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78 % of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36 % of non-brainstem gliomas carrying either K27M or G34R/V mutations. Although mutations in many chromatin modifiers have been identified in cancer, this was the first demonstration that histone mutations may be drivers of disease. Subsequent studies have identified high-frequency mutation of histone H3 to K36M in chondroblastomas and to G34W/L in giant cell tumors of bone, which are diseases of adolescents and young adults. Interestingly, the G34 mutations, the K36M mutations, and the majority of K27M mutations occur in genes encoding the replacement histone H3.3. Here, we review the peculiar characteristics of histone H3.3 and use this information as a backdrop to highlight current thinking about how the identified mutations may contribute to disease development.

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Figures

Fig. 1

Fig. 1

Histone H3.3 shows amino acid differences with H3.1 that promote binding to distinct chaperones. a Sequence alignment of human H3.3, H3.2, and H3.1, with sequence differences in H3.3 marked in red. b Cartoon of chromosome depicting regions of H3.3 incorporation into chromatin and the chaperones responsible

Fig. 2

Fig. 2

Specific histone H3 mutants arise in distinct regions of the brain or in different skeletal tissues and show variable age of presentation. a The amino acids that substitute glycine at amino acid 34 or lysine at amino acids 27 and 36 of histone H3, their properties, and possible posttranslational modifications. b Cartoon depicting the different anatomical location of brain tumors bearing K27M mutant H3.1 or H3.3 and G34R or G34V mutant H3.3. K27M mutants are predominantly found in midline structures (including the thalamus, pons, and brainstem), whereas the G34 mutant tumors are most commonly located in the cerebral hemispheres (Sturm et al. ; Bjerke et al. 2013). c Cartoon illustrating the distribution of different histone H3 mutants in chondroblastomas and giant cell tumors of bone (Behjati et al. 2013). d Graphical representation of span of age of presentation for histone H3 mutant tumors (Schwartzentruber et al. ; Sturm et al. ; Behjati et al. 2013)

Fig. 3

Fig. 3

Codon usage in histone H3.3 and H3.1 genes at the sites of histone mutation. Orange-shaded boxes mark the genes in which mutations are prevalent for the different amino acid substitutions

Fig. 4

Fig. 4

K27M mutants dominantly block PRC2 methyltransferase activity on H3K27, whereas G34R/V mutants block SETD2 methyltransferase function on K36 of the same tail. a Representation of the amino terminal tail of histone H3.3 showing the position of known posttranslational modifications, the site of amino acid substitutions identified in tumors (K27 and G34: red), and the amino acid that differs in the H3.3 tail from H3.1 (Ser 31: orange). b Cartoon depicting the distinct modes of action of K27M mutants and G34R/V mutants in modulating posttranslational modifications on H3 proteins. Note that for the K27M mutant, we depict EZH2 as bound to mutant chromatin, with methyltransferase activity blocked on adjacent sites. Such binding of EZH2 ON chromatin may block the chromatin template from additional chromatin transactions. An alternative possibility is that non-nucleosomal K27M mutant H3 could sequester EZH2 off chromatin, which would leave open the possibility of additional modifications occurring on the mutant chromatin template

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References

    1. Adam S, Polo SE, Almouzni G. Transcription recovery after DNA damage requires chromatin priming by the H3.3 histone chaperone HIRA. Cell. 2013;155:94–106. - PubMed
    1. Adam S, Polo SE, Almouzni G. How to restore chromatin structure and function in response to DNA damage—let the chaperones play: delivered on 9 July 2013 at the 38th FEBS Congress in St Petersburg, Russia. FEBS J. 2014;281:2315–2323. - PubMed
    1. Ahmad K, Henikoff S. The histone variant H3.3 marks active chromatin by replication-independent nucleosome assembly. Mol Cell. 2002;9:1191–1200. - PubMed
    1. Banaszynski LA, Wen D, Dewell S, Whitcomb SJ, Lin M, Diaz N, Elsasser SJ, Chapgier A, Goldberg AD, Canaani E, Rafii S, Zheng D, Allis CD. Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells. Cell. 2013;155:107–120. - PMC - PubMed
    1. Bechet D, Gielen GG, Korshunov A, Pfister SM, Rousso C, Faury D, Fiset PO, Benlimane N, Lewis PW, Lu C, David AC, Kieran MW, Ligon KL, Pietsch T, Ellezam B, Albrecht S, Jabado N. Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas. Acta Neuropathol. 2014;128:733–741. - PMC - PubMed

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