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EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia

A Corrigendum to this article was published on 26 August 2014

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Abstract

The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased trimethylation of histone H3 on Lys27 (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) is also important in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3 in ATM deficiency. Chromatin immunoprecipitation and sequencing showed an increase in H3K27me3 'marks' and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle reentry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescued Purkinje cell degeneration and behavioral abnormalities in Atm−/− mice, demonstrating that EZH2 hyperactivity is another key factor in A-T neurodegeneration.

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Figure 1: Hypermethylation of H3K27 in human A-T and mouse Atm−/− cerebellum.
Figure 2: ATM-mediated EZH2 phosphorylation prevents PRC2 formation and H3K27 methylation.
Figure 3: Shifted H3K27me3 chromatin-binding pattern is related to downregulated neuronal genes in Atm−/− mouse cerebellum.
Figure 4: ATM-dependent EZH2 phosphorylation affects neuronal cell cycle and DNA damage response.
Figure 5: Knockdown of EZH2 prevents cell death and cell cycle reentry in Atm−/− neurons.
Figure 6: Knockdown of EZH2 prevents neurodegeneration of Atm−/− mice.
Figure 7: Effect of ATM-dependent EZH2 phosphorylation on the degeneration of Purkinje cell.
Figure 8: Knockdown of EZH2 reverses neurological behavioral abnormalities of Atm−/− mice.

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  • 30 May 2014

    In the version of this article initially published, red and blue were switched in the key and legend for Figure 3a. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank Y. Xu (University of California, San Diego) for providing the Atmtm1Bal mutant strain. We thank R. Gatti (University of California, Los Angeles) for sharing human A-T paraffin-embedded samples. Human frozen tissue was obtained from NICHD Brain and Tissue Bank of Developmental Disorders at the University of Maryland, Baltimore. Special thanks to R. Ma for the help in stereological analysis of Purkinje cells. We thank M.B. Kastan (Duke University), H. Huang (State University of New York at Stony Brook) and M.-c. Hung (University of Texas M.D. Anderson Cancer Center) for providing the Flag-ATM, myc-EZH2 and GST-EZH2 plasmids, respectively. The long-term support of the A-T Children's Project is gratefully acknowledged, as is the support of Rutgers University and the Hong Kong University of Science and Technology. This work was also funded by grants from the US National Institutes of Health: NS20591 and NS71022 to K.H.; RC1 CA147187 to R.P.H., and MH60706 and NIEHS P30 ES05022 to A.K.

Author information

Authors and Affiliations

Authors

Contributions

J.L. and K.H. designed the experiments, analyzed data and wrote the manuscript. J.L. carried out biochemistry experiments and ChIP-qPCR and semiquantitative PCR. M.R.S. and R.P.H. developed, carried out and analyzed data for ChIPseq analyses. J.L., E.M.M. and A.K. carried out the mouse cerebellar lentiviral injections and behavioral tests.

Corresponding authors

Correspondence to Jiali Li or Karl Herrup.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Elevated H3K27me3 was found in other Atm-/- brain regions

a) Ten micron cryostat sections of wild type and Atm-/- mouse neocortex and hippocampus were immunostained with H3K27me3 and H3K9me3. b) Co-immunoprecipitations show the enhanced interaction between EZH2 and H3K27me3 in A-T brain. Nuclear protein extracts from both control and A-T human cerebellum were immunoprecipitated with EZH2 and blotted with anti-H3K27me3 and anti-EZH2. c) Co-immunoprecipitations show the enhanced interaction between EZH2 and H3K27me3 in Atm-/- mouse brain. Nuclear protein extracts from wild type and Atm-/- mouse cerebellum were immunoprecipitated with EZH2 and blotted with anti-H3K27me3 and anti-EZH2

Supplementary Figure 2 Elevated EZH2 was found in A-T and Atm-/- brain

a) Paraffin sections of human cerebellar cortex from individuals who died with no known brain disease or with a diagnosis of A-T as well as ten micron cryostat sections of wild type and Atm-/- mouse cerebellum were immunostained with EZH2. Scale bar, 50μm. b) Ten micron cryostat sections of wild type and Atm-/- mouse brain were immunostained with EZH2. c) Total RNA was extracted from 3-month wild type and Atm-/- mouse cerebellum; reverse transcription, and PCR amplification was performed as described. Representative blots show the amplified PCR fragments of ezh2 and ezh1 gene at 30 cycles. This analysis suggests that the levels of ezh2 message are not altered in Atm-/- mice. d) Quantification of RT-PCR products such as those illustrated in c). Each bar represents the average of three independent experiments; error bars denote SEM

Supplementary Figure 3 ATM-dependent phosphorylation of EZH2 affects its degradation

a) EZH2 degradation is slower in ATM-deficiency. Human control and A-T fibroblast cells were treated with cycloheximide (CHX) for different times, following which cell lysates were made and probed on Western blots with EZH2 antibody. β–actin was used as a loading control. b) A log plot of the EZH2 protein decay, calculated by linear regression, estimates the half-life as the log (2)/slope. In both genotypes the regression fit is highly significant (p=1.26 x 10-11 for control and 3.18 x 10-13 for A-T fibroblasts). The estimated half-lives were 17.3 hrs (95% CI 15.5-19.6 hrs) for Atm+/+ and 48.0 hrs (95% CI 44.0-52.8 hrs) for Atm-/-. c-d) GFP-EZH2 wild type (WT) and its mutants (2SA and 2SD) were overexpressed in N2a cells followed by treatment with ALLN (10μM) at different times after 24 hours transfection. β–actin was control.

Supplementary Figure 4 H3K27me3 ChIPseq shows genome-wide hypermethylation in Atm-/- mouse cerebellum

a) Overlap of H3K27me3 ChIP-seq alignment and peaks from wild type and Atm-/- mouse cerebella. Peaks were considered to be overlapping if they were within 1 kb of each other. b) To show that H3K27me3 peaks were distributed over the entire genome, the number of peaks per bin (set to 1% of genome) was graphed over genome position. Here, the numbers of peaks per bin were normalized by chromosome to highlight genome coverage.

Supplementary Figure 5 Elevated H3K27me3 links to cell cycle reentry in ATM deficiency

a) Semi-quantitative RT-PCRs from product of H3K27me3 ChIP show increased enrichment of H3K27me3 binding to promoter regions of cdkn2a and cdkn2b in Atm-/- cerebellum. b)Following ChIP with total H3 or H3K27me3 antibody from wild-type and Atm-/- cerebellum, quantitative real-time PCR analysis was performed for the presence of cdkn2a and cdkn2b (* = p < 0.01). gapdh was used as a control. All q-PCR primers are listed in Table S4.

Supplementary Figure 6 The direct effect of the decreased EZH2-mediated H3K27me3 on neuronal gene expression

a) Knocking down of EZH2 reduced H3K27me3 in Atm-/- neurons. Nuclear protein extracts from wild type and Atm-/- neurons with shezh2 infection were assayed by Western blot for the presence of H3K27me3, H3K9me3 and EZH2. b) Total RNA was extracted from wild type and Atm-/- primary neurons after the indicated shRNAs infection. Reverse transcription, and PCR amplification was performed as described. Representative blots show the amplified PCR fragments of target genes at 30 cycles. c-d) Quantitative real-time polymerase chain reaction (PCR) was performed with specific primers for target genes. Data represent the mean ± SD of three independent experiments.

Supplementary Figure 7 The efficiency of lentiviral Ezh2 siRNA-GFP

a) Images of GFP in mice cerebellum show the efficiency of gene transfer. ezh2 siRNA-GFP (shezh2) lentivirus were injected into mouse cerebellum at postnatal day18 (P18); animals were sacrificed for analysis after 3-4 weeks. b) Representative images of EZH2 and H3K27me3 immunostained cerebellum show the efficiency of shezh2 knockdown.

Supplementary Figure 8 Knockdown of EZH2 prevents neurodegeneration in ATM-deficient cerebellum

a) Representative images of PCNA-stained Purkinje cells show the effects of lentiviral delivery of shezh1 and shezh2 on degenerative progression in Atm-/- mouse cerebellum. Brain sections collected 1 week after injection were immunostained with PCNA. Scale bar, 50μm. b) Representative images of H&E staining show the effects of lentiviral delivery of shezh1 and shezh2 on the degenerative progression in Atm-/- mouse cerebellum. Brain sections collected 3 weeks after injection were stained with hematoxylin and eosin (H&E). The white arrows mark Purkinje cells with abnormal vacuoles. Scale bar = 50μm.

Supplementary Figure 9 The patterns of cerebellar foliation or cytoarchitecture in wild-type and Atm−/− mice

These Golgi impregnated sections illustrate the similarities in the patterns of cerebellar foliation in cytoarchitecture in wild type(top) and Atm-/- (bottom) mice. Scale bar= 0.5 mm.

Supplementary Figure 10 Verification of Ezh2 shRNA specificity

Western blots of N2a and SH-SY5Y cell lysates showed specific ezh2 shRNAs exclusively against mouse endogenous EZH2. Protein extracts were from N2a cells (rodent) and SH-SY5Y infected with EZH2 (human) and ezh2 shRNA and blotted with non-specific or human specific EZH2 antibodies.

Supplementary Figure 11 Comparison of H3K27me3 and HDAC4 ChIPseq alignment and peaks from wild-type and Atm−/− mouse cerebella

a) Overlapping peaks in wild type mouse cerebella. b) Overlapping peaks in Atm-/- mouse cerebella. c) Numbers of peaks found within 100 kb upstream of, or within, a gene during bootstrap analysis. The density curve shows the distribution of 100 random simulations and the actual number from the intersection (arrow) of the Atm-/- peaks. As described in the text, random simulations selected 11,766 peaks from the union set of peaks marked with either H3K27me3 or HDAC4 in Atm-/- mouse cerebella (b). The mean distribution of distance filtered peaks from the randomly-selected subsets was 6,201 while the actual intersection group was an average of 6,640, or about 8 x SD from the mean of the random group. Finding more peaks within a reasonable distance of a gene is consistent with the H3K27me3-HDAC4 intersection group being more likely to be binding within cis-acting regulatory sequences than any random subset of all peaks.

Supplementary Figure 12 Full-length pictures of the blots presented in the main figures

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–10 and Supplementary Figures 1–12 (PDF 3015 kb)

Supplementary Table 1

Gene ontology analysis of genes nearest H3K27me3 peaks (DOCX 97 kb)

Supplementary Table 2 and 3

Top 25 Down- and Up-Regulated Genes in Atm-/- mouse cerebellum (DOCX 75 kb)

Supplementary Table 4

Gene ontology of downregulated genes in Atm-/- mouse cerebellum (DOCX 134 kb)

Supplementary Table 5

The coefficient of (CE) for the number of counted Purkinje cells in the cerebella (mean) of ATM mutant mice (DOCX 150 kb)

Supplementary Table 6

Target Sequences of lentiviral shRNAs (DOCX 409 kb)

Supplementary Table 7

Target Sequences of piLenti-siRNA-GFP (DOCX 27 kb)

Supplementary Table 8

Sequences of ChIP quantitative Real time PCR primers (DOCX 32 kb)

Supplementary Table 9

Sequences of ChIP quantitative Real time PCR primers (DOCX 23 kb)

Supplementary Table 10

Target Sequences of piLenti-siRNA-GFP (DOCX 25 kb)

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Li, J., Hart, R., Mallimo, E. et al. EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia. Nat Neurosci 16, 1745–1753 (2013). https://doi.org/10.1038/nn.3564

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