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 Wijnen; Andre M. Oliveira; Rui Ming Xu; Jennifer J. Westendorf; Zhiguo Zhang

doi:10.1126/science.aae0065

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

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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 language	English (US)
Pages (from-to)	1344-1348
Number of pages	5
Journal	Science
Volume	352
Issue number	6291
DOIs	https://doi.org/10.1126/science.aae0065
State	Published - Jun 10 2016

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Fang, D., Gan, H., Lee, J. H., Han, J., Wang, Z., Riester, S. M., Jin, L., Chen, J., Zhou, H., Wang, J., Zhang, H., Yang, N., Bradley, E. W., Ho, T. H., Rubin, B. P., Bridge, J. A., Thibodeau, S. N., Ordog, T., Chen, Y., ... 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

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

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title = "The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas",

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.",

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

year = "2016",

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doi = "10.1126/science.aae0065",

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T1 - The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas

AU - Fang, Dong

AU - Gan, Haiyun

AU - Lee, Jeong Heon

AU - Han, Jing

AU - Wang, Zhiquan

AU - Riester, Scott M.

AU - Jin, Long

AU - Chen, Jianji

AU - Zhou, Hui

AU - Wang, Jinglong

AU - Zhang, Honglian

AU - Yang, Na

AU - Bradley, Elizabeth W.

AU - Ho, Thai H.

AU - Rubin, Brian P.

AU - Bridge, Julia A.

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

PY - 2016/6/10

Y1 - 2016/6/10

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

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