Whole-genome sequencing data mining efforts have revealed numerous histone mutations in a wide range of cancer types. These occur in all four core histones in both the tail and globular domains and remain largely uncharacterized. Here we used two high-throughput approaches, a DNA-barcoded mononucleosome library and a humanized yeast library, to profile the biochemical and cellular effects of these mutations. We identified cancer-associated mutations in the histone globular domains that enhance fundamental chromatin remodeling processes, histone exchange and nucleosome sliding, and are lethal in yeast. In mammalian cells, these mutations upregulate cancer-associated gene pathways and inhibit cellular differentiation by altering expression of lineage-specific transcription factors. This work represents a comprehensive functional analysis of the histone mutational landscape in human cancers and leads to a model in which histone mutations that perturb nucleosome remodeling may contribute to disease development and/or progression.
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RNA-seq raw data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE146959. Source data are provided with this paper. All other data are included within this paper, Extended Data and Supplementary Information files.
A custom R script was used to count individual DNA barcodes from sequencing data in MN library experiments and was previously reported24. Custom Python (v.2.7.10) scripts were used to fit and determine Thalf values in MN thermal stability experiments and to calculate kobs values in ACF remodeling experiments are available at https://github.com/jdbagert/oncohistonelibrary.
Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17, 487–500 (2016).
Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).
Mohammad, F. & Helin, K. Oncohistones: drivers of pediatric cancers. Genes Dev. 31, 2313–2324 (2018).
Weinberg, D. N., Allis, C. D. & Lu, C. Oncogenic mechanisms of histone H3 mutations. Cold Spring Harb. Perspect. Med. 7, a026443 (2017).
Behjati, S. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat. Genet. 45, 1479–1482 (2013).
Lu, C. et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352, 844–849 (2016).
Presneau, N. et al. Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast-rich mimics. J. Pathol. Clin. Res. 1, 113–123 (2015).
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012).
Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).
Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).
Brown, Z. Z. et al. Strategy for ‘detoxification’ of a cancer-derived histone mutant based on mapping its interaction with the methyltransferase PRC2. J. Am. Chem. Soc. 136, 13498–13501 (2014).
Chan, K. M. et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 27, 985–990 (2013).
Fang, D. et al. The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science 352, 1344–1348 (2016).
Lohr, J. G. et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc. Natl Acad. Sci. USA 109, 3879–3884 (2012).
Papillon-Cavanagh, S. et al. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nat. Genet. 49, 180–185 (2017).
Zhao, S. et al. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition. Proc. Natl Acad. Sci. USA 113, 12238–12243 (2016).
Boileau, M. et al. Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness. Nat. Commun. 10, 2891 (2019).
Nacev, B. A. et al. The expanding landscape of ‘oncohistone’ mutations in human cancers. Nature 567, 473–478 (2019).
Bennett, R. L. et al. A mutation in histone H2B represents a new class of oncogenic driver. Cancer Discov. 9, 1438–1451 (2019).
Arimura, Y. et al. Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome. Nucleic Acids Res. 46, 10007–10018 (2018).
Wan, Y. C. E. et al. Cancer-associated histone mutation H2BG53D disrupts DNA–histone octamer interaction and promotes oncogenic phenotypes. Signal Transduct. Target. Ther. 5, 27 (2020).
Nguyen, U. T. T. et al. Accelerated chromatin biochemistry using DNA-barcoded nucleosome libraries. Nat. Methods 11, 834–840 (2014).
Dann, G. P. et al. ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference. Nature 548, 607–611 (2017).
Nakanishi, S. et al. A comprehensive library of histone mutants identifies nucleosomal residues required for H3K4 methylation. Nat. Struct. Mol. Biol. 15, 881–888 (2008).
Dai, J. et al. Probing nucleosome function: a highly versatile library of synthetic histone H3 and H4 mutants. Cell 134, 1066–1078 (2008).
Truong, D. M. & Boeke, J. D. Resetting the yeast epigenome with human nucleosomes. Cell 171, 1508–1519 (2017).
Park, Y. J., Chodaparambil, J. V., Bao, Y., McBryant, S. J. & Luger, K. Nucleosome assembly protein 1 exchanges histone H2A-H2B dimers and assists nucleosome sliding. J. Biol. Chem. 280, 1817–1825 (2005).
Levendosky, R. F., Sabantsev, A., Deindl, S. & Bowman, G. D. The Chd1 chromatin remodeler shifts hexasomes unidirectionally. eLife 5, e21356 (2016).
Stevens, A. J. et al. Design of a split intein with exceptional protein splicing activity. J. Am. Chem. Soc. 138, 2162–2165 (2016).
Vila-Perelló, M. et al. Streamlined expressed protein ligation using split inteins. J. Am. Chem. Soc. 135, 286–292 (2013).
Clapier, C. R., Iwasa, J., Cairns, B. R. & Peterson, C. L. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat. Rev. Mol. Cell Biol. 18, 407–422 (2017).
Dao, H. T., Dul, B. E., Dann, G. P., Liszczak, G. P. & Muir, T. W. A basic motif anchoring ISWI to nucleosome acidic patch regulates nucleosome spacing. Nat. Chem. Biol. 16, 134–142 (2020).
Clapier, C. R. & Cairns, B. R. Regulation of ISWI involves inhibitory modules antagonized by nucleosomal epitopes. Nature 492, 280–284 (2012).
Shogren-Knaak, M. et al. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844–847 (2006).
Levendosky, R. F. & Bowman, G. D. Asymmetry between the two acidic patches dictates the direction of nucleosome sliding by the ISWI chromatin remodeler. eLife 8, e45472 (2019).
Zhan, T., Rindtorff, N. & Boutros, M. Wnt signaling in cancer. Oncogene 36, 1461–1473 (2017).
Massagué, J. TGFβ in cancer. Cell 134, 215–230 (2008).
Wong, K. K., Engelman, J. A. & Cantley, L. C. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev. 20, 87–90 (2010).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
Zhuang, L. et al. Depletion of Nsd2-mediated histone H3K36 methylation impairs adipose tissue development and function. Nat. Commun. 9, 1796 (2018).
Farmer, S. R. Transcriptional control of adipocyte formation. Cell Metab. 4, 263–273 (2006).
Albig, C. et al. JASPer controls interphase histone H3S10 phosphorylation by chromosomal kinase JIL-1 in Drosophila. Nat. Commun. 10, 5343 (2019).
Liszczak, G., Diehl, K. L., Dann, G. P. & Muir, T. W. Acetylation blocks DNA damage-induced chromatin ADP-ribosylation. Nat. Chem. Biol. 14, 837–840 (2018).
Wojcik, F. et al. Functional crosstalk between histone H2B ubiquitylation and H2A modifications and variants. Nat. Commun. 9, 1394 (2018).
Horikoshi, N., Arimura, Y., Taguchi, H. & Kurumizaka, H. Crystal structures of heterotypic nucleosomes containing histones H2A.Z and H2A. Open Biol. 6, 160127 (2016).
Lechner, C. C., Agashe, N. D. & Fierz, B. Traceless synthesis of asymmetrically modified bivalent nucleosomes. Angew. Chemie Int. Ed. 55, 2903–2906 (2016).
Voigt, P. et al. Asymmetrically modified nucleosomes. Cell 151, 181–193 (2012).
Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).
Rhee, H. S., Bataille, A. R., Zhang, L. & Pugh, B. F. Subnucleosomal structures and nucleosome asymmetry across a genome. Cell 159, 1377–1388 (2014).
Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).
Dyer, P. N. et al. Reconstitution of nucleosome core particles from recombinant histones and DNA. Methods Enzymol. 375, 23–44 (2003).
Whitcomb, S. J. et al. Histone monoubiquitylation position determines specificity and direction of enzymatic cross-talk with histone methyltransferases Dot1L and PRC2. J. Biol. Chem. 287, 23718–23725 (2012).
Soni, R., Carmichael, J. P. & Murray, J. A. H. Parameters affecting lithium acetate-mediated transformation of Saccharomyces cerevisiae and development of a rapid and simplified procedure. Curr. Genet. 24, 455–459 (1993).
Fierz, B., Kilic, S., Hieb, A. R., Luger, K. & Muir, T. W. Stability of nucleosomes containing homogenously ubiquitylated H2A and H2B prepared using semisynthesis. J. Am. Chem. Soc. 134, 19548–19551 (2012).
Taguchi, H., Horikoshi, N., Arimura, Y. & Kurumizaka, H. A method for evaluating nucleosome stability with a protein-binding fluorescent dye. Methods 70, 119–126 (2014).
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).
Anders, S., Reyes, A. & Huber, W. Detecting differential usage of exons from RNA-seq data. Genome Res. 22, 2008–2017 (2012).
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B. Statistical Methodol. 57, 289–300 (1995).
We thank T. Carroll from the Bioinformatics Resource Center at The Rockefeller University and J. Majewski and E. Bareke from McGill University for help and guidance with the RNA-seq analyses. We thank W. Wang and the Princeton Genomics Core Facility for designing the Illumina adaptor sequences and performing NGS on DNA-barcoded MN library experimental samples. We thank A.J. Burton for providing the dead CfaC peptide and H. Liu for providing Cy3-tagged histone H3. Funding support includes grant nos. P01CA196539 (T.W.M. and C.D.A.) and R37-GM086868 (T.W.M.), and we thank members of the Allis and Muir laboratories, especially those members of our collective P01 team. J.D.B. was funded by a postdoctoral fellowship from the US National Institutes of Health (grant no. GM123659). M.M.M. was funded by a postdoctoral fellowship from the US National Institutes of Health (grant no. GM131632). A.L.P. was funded by an Anderson Graduate Fellowship in Cancer Research from the Anderson Cancer Center. F.W. was supported by a postdoctoral fellowship from the German Research Foundation (WO 2039/1-1). B.A.N. was funded by the National Cancer Institute (grant no. 1K08CA245212) and we acknowledge the Memorial Sloan Kettering Cancer Center Support Grant/Core grant (no. P30 CA008748). L.F. was supported by the C. H. Li Memorial Scholar Fund Award.
The authors declare no competing interests.
Peer review information Nature Chemical Biology thanks Andrew Andrews, Suzanne Baker and other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended Data Fig. 1 Selection criteria for histone mutations to include in high-throughput libraries.
a, Distributions of histone mutations (tumor mutational burden ≤ 10) across the four canonical histones were fit to a Poisson distribution (red line) to identify sites of outlier mutational frequency (p < 0.05, red bars). b, The set of amino acid mutations observed at each histone site was assessed for overrepresentation of specific histone mutations, adjusting for codon bias. Mutants with a Benjamini FDR-adjusted p-value < 0.03 are shown in red.
Extended Data Fig. 2 Generation of a barcoded MN library for high-throughput profiling of histone mutations.
a, Schematic of barcoded MN library assembly and use in in vitro ChIP-seq assays. b, Native gel analysis of individually assembled barcoded MNs that were combined to create the nucleosome library (see panel c). c, Native gel analysis of the DNA-barcoded mutant MN library. The upper band shows the combined signal from all assembled MNs included in the library. The lower band shows free DNA from nonnucleosomal DNA controls. d, Assessment of quality of MN library members by deep sequencing, as determined by the amount of free barcoded DNA associated with each member. The plot shows normalized reads from library aliquots that were either treated with PstI restriction enzyme or untreated. The cuttable DNA control, as well as DNA exposed as a result of poor nucleosome assembly, are digested in the PstI-treated sample and thus exhibit lower read counts. The black line represents an idealized scenario in which all MNs are 100% assembled (y = x). This function yields an R2 value of 0.98, indicating that MN library members are well-assembled in the library. Data are presented as the mean ± s.d. (n = 3). e, Unstable nucleosomes (H2BE76K20,21) do not exhibit spontaneous exchange of DNA with fluorescently labeled nucleosomes, even under conditions of biased stoichiometry and high temperature. Samples containing individual or mixtures of unlabeled H2BE76K MNs and fluorescently tagged (H2B-Fluor) MNs were incubated at the indicated temperatures for 1 h and then assessed by native gel electrophoresis to determine whether exchange of fluorescent histones occurs. Numbers indicate ratios of MNs in a given sample. H2BE76K MNs were assembled on DNA with a 15 bp 3’ overhang (15 bp 3’OH), whereas H2B-Fluor MNs were assembled on DNA with no 3’ overhang (0 bp 3’OH) so the two species could be distinguished based on differential gel migration. Additionally, H2B-Fluor MNs were assembled on DNA with a 15 bp 3’ overhang as a positive control for DNA exchange. Source data
Extended Data Fig. 3 Structurally perturbative histone mutations cause growth defects in humanized yeast.
a, A humanized yeast library facilitates high-throughput analysis of the effects of histone mutations on yeast viability. A plasmid shuffle assay is used to select for yeast that can subsist solely on mutant human histones. b, Serial dilutions of humanized yeast with mutant histones after 5FOA selection. Control cells are grown without 5FOA to show strain growth prior to selection for human histones. c, Yeast carrying wild-type and select histone mutants show similar growth rates prior to 5FOA selection. This indicates that growth differences observed on 5FOA plates are not attributable to differential growth rates prior to selection for cells able to subsist solely on mutant human histones.
a, Denaturing gel analysis of purified mouse Nap1. b, Proof-of-concept demonstration of the dimer exchange assay on wild-type and destabilized H2BE76K20,21 mutant MNs using fluorescently labeled dimers and in-gel fluorescence readout. The lower band in the ethidium bromide stain shows partially disassembled nucleosomes, which are observed only when Nap1 is added to nucleosomes without additional H2A/H2B dimers. Fluor, fluorescein. EtBr, ethidium bromide. c, Nucleosomes do not exhibit exchange of H3/H4 tetramers during the Nap1 H2A/H2B dimer exchange assay. Samples containing wild-type MNs or H2BE76K and fluorescently tagged H3 (H3-Cy3) MNs were incubated under Nap1 H2A/H2B dimer exchange conditions (see Methods) and then assessed by native gel electrophoresis to determine whether exchange of fluorescent histones occurs. Numbers indicate the relative ratios of MNs in each sample. Wild-type MNs were assembled on DNA with a 60 bp overhang (60 bp OH), whereas H2BE76K/H3-Cy3 MNs were assembled on DNA with no overhang (0 bp OH), allowing discrimination of the two nucleosome species by gel migration. Additionally, H2BE76K/H3-Cy3 MNs were assembled on DNA with a 60 bp overhang as a positive control for DNA exchange. d, Qubit quantification of MN DNA after affinity purification of nucleosomes that were subjected to the Nap1-mediated dimer exchange assay with biotinylated H2A/H2B dimers. DNA yield displays the fraction of DNA from affinity purified samples relative to input samples, indicating the extent of H2A/H2B dimer exchange. Individual WT and H2BE76K MNs were used as a proof-of-principle demonstration that destabilized MNs result in increased dimer exchange and, by extension, increased MN DNA after affinity purification. DNA yields from barcoded MN library experiments are similar to wild-type MNs, which is consistent with the resulting library data that shows that the majority of mutations have no or only moderate effects on dimer exchange (Fig. 2b). Data are presented as the mean ± s.d. (n = 2 for individual MNs, n = 4 for MN library). e, H2AE56A/K greatly enhance dimer exchange compared to other acidic patch mutations in the histone mutant library. Data are presented as the mean ± s.d. (n = 4). f, Denaturing gel analysis of purified octamers, dimers, and tetramers used to generate individual MNs for follow-up stability assays. g, Native gels of assembled mutant MNs used in follow-up dimer exchange and thermal stability assays. h, Raw data showing enhanced fluorescence for destabilizing mutants in the Nap1-mediated dimer exchange assay. i, Validation of select dimer exchange-enhancing histone mutant MNs via quantification of the in-gel fluorescence data shown in panel h. Data are presented as the mean ± s.d. (n = 3). Values from mutant MNs in e and i exhibit statistically significant differences relative to wild-type (p < 0.05) in a two-sample, unequal variances t-test, unless otherwise noted. ns, not significant. Source data
Extended Data Fig. 5 Destabilizing histone mutations perturb nucleosome thermal stability and octamer assembly.
a, Raw data for Fig. 2f showing the thermal stability of MNs with histone mutations. Data are shown in triplicate with a sigmoidal fit for the dimer melt (see Methods). The Thalf is shown for each fit as a dotted vertical line and reported as the mean ± s.d. (n = 3). b, Fast protein liquid chromatography traces of histone mutants that did not form octamers under standard assembly conditions.
a, Denaturing gel analysis of purified wild-type, mutant, and H2A/H2B-CfaN-streptag dimers. b, Proof-of-concept assembly and purification of heterotypic nucleosomes with ubiquitinated H2B (H2Bub), which allows asymmetric nucleosomes to be distinguished by size. Numbers indicate molecular species shown in Fig. 3a. Hex., hexasomes. Het., heterotypic. c, Assembly and purification of heterotypic (het.) nucleosomes containing H2BE71K and H2BE76K. Assembly of wild-type (effectively homotypic) nucleosomes served as a control for the assembly process. 6/8 refers to hexasomes/octasomes. d, Raw data showing enhanced fluorescence for both homotypic and heterotypic destabilizing mutant MNs in the Nap1-mediated dimer exchange assay. e, Raw data showing the thermal stability of homotypic and heterotypic mutant MNs. Data are shown in triplicate with a sigmoidal fit for the dimer melt. The Thalf is shown for each fit as a dotted vertical line and reported as the mean ± s.d. (n = 3). Source data
Extended Data Fig. 7 Mutations at the histone-DNA interface and the acidic patch alter nucleosome sliding.
a, Denaturing gel showing the two subunits of the purified hACF complex. b, Time-course of ACF remodeling reactions from all MNs in the library both with ATP (red) and without ATP (black) demonstrate that the remodeling rates measured are ATP-dependent. Data are presented as the mean of individual MN values at each time point (n = 3). c, Denaturing gel analysis of histone mutant octamers used to generate individual MNs for follow-up sliding assays. A subset of octamers, also utilized for follow-up dimer exchange and thermal stability assays, were already depicted in Extended Data Fig. 4f. d, Native gels of assembled MNs used in sliding assays. e, Representative gel images (all assays performed in triplicate) showing a time-course of DNA cleavage during ACF sliding in REA assays. f, Observed rate constants for dimer-tetramer interface mutant MNs do not exhibit statistically significant differences relative to wild-type (p > 0.05) in a two-sample, unequal variances t-test. Data are presented as the fit kobs parameter ± s.d. (n = 3). ns, not significant. Source data
Extended Data Fig. 8 Globular domain mutations alter gene expression and impair cell differentiation.
a, Western blot analysis of acid extracted histones from C3H10T1/2 cells stably expressing HA-tagged histone mutants shows mutant incorporation into chromatin. A standard curve of mixtures of murine H2B (mH2B) and tagged murine H2B (mH2B-F-HA) was used to estimate the relative expression of mutant histones, which ranged from 1–17% of the total H2B protein. b, Representative immunofluorescence images of tagged histone mutants expressed in C3H10T1/2 cells. Scale bar, 50 µm. c, Principal component analysis (PCA) of gene expression data from histone mutant cell lines. PCA distinguishes wild-type from mutant cell lines, as well as individual mutations from each other. d, Expression of select cancer-associated genes representing the dysregulated molecular pathways in histone mutant-expressing cell lines as assessed by RT-qPCR (relative to wild type). Data presented are the mean ± s.e.m. (n = 3) and values from mutant cell lines exhibit significant differences relative to wild-type (p < 0.05) in a two-sample t-test, unless otherwise noted. ns, not significant. nd, not detected. e, Mutant and wild-type H2B cell lines were induced to undergo chondrocyte differentiation for 7 days. Representative images are shown after Alcian Blue staining, as well as the quantified Alcian Blue staining of cell extracts, reported as the mean ± s.d. (n = 8). An asterisk marks mutant cell lines that cause a significant reduction in staining compared to both the parent line and to cells expressing wild-type H2B (p < 0.05, unequal variances t-test). Source data
a, Gene ontology (GO) analysis for individual histone mutants showing the top ten upregulated and downregulated KEGG pathways. The dotted line shows the statistical cutoff (Benjamini FDR < 0.05) used for selecting which GO groups to display in Fig. 5b. b, Quantitative analysis showing the relative gene expression values (mutant to wild-type histone) from the significantly regulated GO groups presented in Fig. 5b.
Supplementary Figs. 1 and 2 and Tables 7 and 8.
Histone mutants represented in the barcoded MN and humanized yeast libraries.
Humanized yeast phenotypes (no phenotype, impaired growth or no growth) for each histone mutant included in the library.
Raw data and subsequent calculations from Nap1-mediated dimer exchange experiment on the barcoded MN library.
Raw data and subsequent calculations from ACF remodeling experiment on the barcoded MN library.
RNA-sequencing data for cells expressing mutant and wild-type histones.
Gene ontology analysis of significantly up- and downregulated genes from cells expressing mutant histones.
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Bagert, J.D., Mitchener, M.M., Patriotis, A.L. et al. Oncohistone mutations enhance chromatin remodeling and alter cell fates. Nat Chem Biol 17, 403–411 (2021). https://doi.org/10.1038/s41589-021-00738-1
Nature Chemical Biology (2021)