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 journalArticlepeer-review

156 Scopus citations


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
Issue number6291
StatePublished - Jun 10 2016

Bibliographical note

Funding Information:
We thank M. Goldring for T/C28a2 cells and Z. Lou for plasmids, B. Eckloff and T. Wood for sequencing, and B. Madden for mass spectrometry analysis. These studies were supported by the NIH [grants GM81838 and CA157489 (Z.Z.), AR68103 (J.J.W.), AR65397 (E.W.B.), AR049069 (A.J.v.W.), and DK58185 (T.O.)], the Natural Science Foundation of China [grant 31210103914 (R.-M.X.)], and the Epigenomics Program (Center for Individualized Medicine) of the Mayo Clinic. ChIP-seq and RNA-seq data sets have been deposited into the Gene Expression Omnibus under accession number GSE7523.

Publisher Copyright:
© 2016, American Association for the Advancement of Science. All rights reserved.


Dive into the research topics of 'The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas'. Together they form a unique fingerprint.

Cite this