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

Kallappagoudar S, Yadav RK, Lowe BR, Partridge JF - Chromosoma (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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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Fig4: 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

Mentions: The N-terminal tails of histones are decorated in covalent posttranslational modifications which can modulate the accessibility of the underlying DNA for diverse chromatin transactions such as transcriptional control, chromosome segregation, and the repair of DNA damage. Modifications on the tail of histone H3 are well documented (Fig. 4a), and the K27M missense mutation has generated much interest due to studies which suggest it plays a dominant role in blocking the accumulation of repressive H3K27 methyl marks (Bender et al. 2013; Lewis et al. 2013; Venneti et al. 2013; Chan et al. 2013). Genomic H3K27 methylation is regulated by the Polycomb group (PcG) of proteins. PcG are evolutionarily conserved proteins which have roles ranging from seed development in plants, X-chromosome inactivation in mammals to maintenance of identity in stem cells. These complexes epigenetically regulate transcriptional states by modulating the H3K27Me3 and H2AK119Ub1 histone marks. In Drosophila, PcG proteins interact with PREs to establish cellular memory modules and are involved in developmental determination of body plan by repressing homeotic genes (reviewed in (Di and Helin 2013; Grossniklaus and Paro 2014)). While PRE-like elements in mammals have been reported (Sing et al. 2009; Woo et al. 2010; Cuddapah et al. 2012; Bengani et al. 2013; Woo et al. 2013), their nature and functional relevance are subject to debate. H3K27 is an important target of PRC2 (Polycomb repressive complex 2) complexes that contain EZH2 or EZH1 histone methyl transferases. Indeed in Drosophila, K27 has been demonstrated to be a critical target for PRC2 since replacement of the histone H3 cluster with an H3K27R transgene mimicked the phenotype of loss of PRC2 activity (Pengelly et al. 2013), even in the context of a wild-type H3.3 genetic background.Fig. 4


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

Kallappagoudar S, Yadav RK, Lowe BR, Partridge JF - Chromosoma (2015)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig4: 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
Mentions: The N-terminal tails of histones are decorated in covalent posttranslational modifications which can modulate the accessibility of the underlying DNA for diverse chromatin transactions such as transcriptional control, chromosome segregation, and the repair of DNA damage. Modifications on the tail of histone H3 are well documented (Fig. 4a), and the K27M missense mutation has generated much interest due to studies which suggest it plays a dominant role in blocking the accumulation of repressive H3K27 methyl marks (Bender et al. 2013; Lewis et al. 2013; Venneti et al. 2013; Chan et al. 2013). Genomic H3K27 methylation is regulated by the Polycomb group (PcG) of proteins. PcG are evolutionarily conserved proteins which have roles ranging from seed development in plants, X-chromosome inactivation in mammals to maintenance of identity in stem cells. These complexes epigenetically regulate transcriptional states by modulating the H3K27Me3 and H2AK119Ub1 histone marks. In Drosophila, PcG proteins interact with PREs to establish cellular memory modules and are involved in developmental determination of body plan by repressing homeotic genes (reviewed in (Di and Helin 2013; Grossniklaus and Paro 2014)). While PRE-like elements in mammals have been reported (Sing et al. 2009; Woo et al. 2010; Cuddapah et al. 2012; Bengani et al. 2013; Woo et al. 2013), their nature and functional relevance are subject to debate. H3K27 is an important target of PRC2 (Polycomb repressive complex 2) complexes that contain EZH2 or EZH1 histone methyl transferases. Indeed in Drosophila, K27 has been demonstrated to be a critical target for PRC2 since replacement of the histone H3 cluster with an H3K27R transgene mimicked the phenotype of loss of PRC2 activity (Pengelly et al. 2013), even in the context of a wild-type H3.3 genetic background.Fig. 4

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.

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.

No MeSH data available.


Related in: MedlinePlus