The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas

Dong Fang, Haiyun Gan, Jeong Heon Lee, Jing Han, Zhiquan Wang, Scott M. Riester, Long Jin, Jianji Chen, Hui Zhou, Jinglong Wang, Honglian Zhang, Na Yang, Elizabeth W. Bradley, Thai H. Ho, Brian P. Rubin, Julia A. Bridge, Stephen N. Thibodeau, Tamas Ordog, Yue Chen, Andre J. Van WijnenAndre M. Oliveira, Rui Ming Xu, Jennifer J. Westendorf, Zhiguo Zhang

Research output: Contribution to journalArticle

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Abstract

More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells, including increased ability to form colonies, resistance to apoptosis, and defects in differentiation. Thus, H3.3K36M proteins reprogram the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes.

Original languageEnglish (US)
Pages (from-to)1344-1348
Number of pages5
JournalScience
Volume352
Issue number6291
DOIs
StatePublished - Jun 10 2016

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Chondroblastoma
Chondrocytes
Histones
Methylation
Mutation
Neoplasm Genes
Methyltransferases
Mutant Proteins
Methionine
Lysine
Neoplasms
Carcinogenesis
Apoptosis
Genes
Proteins

ASJC Scopus subject areas

  • General

Cite this

Fang, D., Gan, H., Lee, J. H., Han, J., Wang, Z., Riester, S. M., ... Zhang, Z. (2016). The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science, 352(6291), 1344-1348. https://doi.org/10.1126/science.aae0065

The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. / Fang, Dong; Gan, Haiyun; Lee, Jeong Heon; Han, Jing; Wang, Zhiquan; Riester, Scott M.; Jin, Long; Chen, Jianji; Zhou, Hui; Wang, Jinglong; Zhang, Honglian; Yang, Na; Bradley, Elizabeth W.; Ho, Thai H.; Rubin, Brian P.; Bridge, Julia A.; Thibodeau, Stephen N.; Ordog, Tamas; Chen, Yue; Van Wijnen, Andre J.; Oliveira, Andre M.; Xu, Rui Ming; Westendorf, Jennifer J.; Zhang, Zhiguo.

In: Science, Vol. 352, No. 6291, 10.06.2016, p. 1344-1348.

Research output: Contribution to journalArticle

Fang, D, Gan, H, Lee, JH, Han, J, Wang, Z, Riester, SM, Jin, L, Chen, J, Zhou, H, Wang, J, Zhang, H, Yang, N, Bradley, EW, Ho, TH, Rubin, BP, Bridge, JA, Thibodeau, SN, Ordog, T, Chen, Y, Van Wijnen, AJ, Oliveira, AM, Xu, RM, Westendorf, JJ & Zhang, Z 2016, 'The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas', Science, vol. 352, no. 6291, pp. 1344-1348. https://doi.org/10.1126/science.aae0065
Fang D, Gan H, Lee JH, Han J, Wang Z, Riester SM et al. The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science. 2016 Jun 10;352(6291):1344-1348. https://doi.org/10.1126/science.aae0065
Fang, Dong ; Gan, Haiyun ; Lee, Jeong Heon ; Han, Jing ; Wang, Zhiquan ; Riester, Scott M. ; Jin, Long ; Chen, Jianji ; Zhou, Hui ; Wang, Jinglong ; Zhang, Honglian ; Yang, Na ; Bradley, Elizabeth W. ; Ho, Thai H. ; Rubin, Brian P. ; Bridge, Julia A. ; Thibodeau, Stephen N. ; Ordog, Tamas ; Chen, Yue ; Van Wijnen, Andre J. ; Oliveira, Andre M. ; Xu, Rui Ming ; Westendorf, Jennifer J. ; Zhang, Zhiguo. / The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. In: Science. 2016 ; Vol. 352, No. 6291. pp. 1344-1348.
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abstract = "More than 90{\%} of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells, including increased ability to form colonies, resistance to apoptosis, and defects in differentiation. Thus, H3.3K36M proteins reprogram the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes.",
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AU - Gan, Haiyun

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AU - Riester, Scott M.

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AU - Chen, Jianji

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AU - Rubin, Brian P.

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AU - Thibodeau, Stephen N.

AU - Ordog, Tamas

AU - Chen, Yue

AU - Van Wijnen, Andre J.

AU - Oliveira, Andre M.

AU - Xu, Rui Ming

AU - Westendorf, Jennifer J.

AU - Zhang, Zhiguo

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N2 - More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells, including increased ability to form colonies, resistance to apoptosis, and defects in differentiation. Thus, H3.3K36M proteins reprogram the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes.

AB - More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells, including increased ability to form colonies, resistance to apoptosis, and defects in differentiation. Thus, H3.3K36M proteins reprogram the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes.

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