Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration
Open accessAbstract
Normal brain function depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. Neuronal specification is driven by transcriptional programs that are established during early neuronal development and remain in place in the adult brain. The fidelity of neuronal specification depends on the robustness of the transcriptional program that supports the neuron type-specific gene expression patterns. Here we show that polycomb repressive complex 2 (PRC2), which supports neuron specification during differentiation, contributes to the suppression of a transcriptional program that is detrimental to adult neuron function and survival. We show that PRC2 deficiency in striatal neurons leads to the de-repression of selected, predominantly bivalent PRC2 target genes that are dominated by self-regulating transcription factors normally suppressed in these neurons. The transcriptional changes in PRC2-deficient neurons lead to progressive and fatal neurodegeneration in mice. Our results point to a key role of PRC2 in protecting neurons against degeneration.
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PRC2 silences genes involved in neurodegeneration and its deficiency leads to de-repression of developmental regulators such as Hox gene clusters, which manifest in progressive and fatal neurodegeneration in mice.
“PRC2 silences genes involved in neurodegeneration and its deficiency leads to the de-repression of developmental regulators such as the Hox gene clusters, which manifest in progressive and fatal neurodegeneration in mice [54].”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [54]
Deficiency in Eed and loss of H3K27me3 led to up-regulation of known PRC2 targets such as Tbx15 and Hoxd8, but did not affect expression of genes defining microglia lineage identity or genes characteristic of pro-inflammatory activation.
“The deficiency in Eed and the ensuing loss of H3K27me3 led to the up-regulation of several known PRC2 targets, such as Tbx15 and Hoxd830,31 (Fig. 5g,h, Supplementary Fig. 11f,g, Supplementary Table 8,9), but did not affect the expression of genes that define microglia lineage identity (Supplementary Fig. 11f,g, Supplementary Table 8,9) or genes characteristic of microglia pro-inflammatory”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [31]
The lag between PRC2 loss and induction of its target genes in stMg, cxMg, and cbMg resembles prior neuronal findings and probably reflects slow H3 turnover plus slow KDM6A/B catalysis.
“The delay between the inactivation of PRC2 and PRC2-target gene induction in stMg, cxMg, and cbMg mimics our previous findings in neurons and is likely based on the combination of slow histone H3 protein turnover, as well as the slow catalytic activity of the H3K27me3 demethylases, KDM6A/B31.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [31]
The sample sizes used in the study were similar to those reported in previous publications.
“No statistical methods were used to pre-determine sample sizes but our sample sizes are similar to those reported in previous publications19,31,95,99,108.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [31]
Previous studies on Huntington's disease have consistently detected signs of neuronal epigenetic instability.
“Previous studies on Huntington’s disease have consistently detected signs of neuronal epigenetic instability (Ayata et al., 2018; von Schimmelmann et al., 2016).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as von Schimmelmann et al., 2016
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“Additionally, neuronal activation can lead to the phosphorylation of histone H3 at serine 28 (H3S28) followed by the dissociation of the PRC2 from chromatin and an ensuing loss of H3K27me3 10 .”
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G9a influences neuronal subtype specification in striatum
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Self-citationIN VIVO METHYLATION AND TURNOVER OF RAT BRAIN HISTONES
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The roles and regulation of Polycomb complexes in neural development
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“Much of the negative gene regulation in developing neurons is achieved by the Polycomb repressive complex 2 (PRC2) 4 .”
Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice
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“Moreover, the expression of mutant huntingtin in mouse ES cells or neuronal progenitor cells (NPCs) alters the pattern of genome-wide H3K27me3 distribution in both cell types 15 .”
The Role of H3K4me3 in Transcriptional Regulation Is Altered in Huntington’s Disease
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“The possible link between PRC2 and HD is further supported by the loss of neuronal PRC2/H3K27me3 sites 14 and the up-regulation of some of the PRC2 target genes in the HD affected human brain 14,16,17 .”
InfluentialSödersten, E., Feyder, M. T., Lerdrup, M., Gomes, A.-L. R., Kryh, H., Spigolon, G., Caboche, J., Fisone, G., & Hansen, K. H. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004574 · Cited by 52 · cited 2× · see citing works
“Changes in PRC2 activity and alterations in H3K27me3 levels and distribution have recently been implicated in several human neurodegenerative diseases 11,12 , including Huntington disease (HD) 13,14 .”
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Network2Canvas: network visualization on a canvas with enrichment analysis
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“As discussed, changes in PRC2 function could be triggered either transiently, by non-persisting events such as seizures 50 , or permanently, by the expression of pathogenic proteins such as mutant huntingtin protein, which can directly interfere with PRC2 recruitment and function 13,14 .”
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Negative feedback control of neuronal activity by microglia
Badimon, A., Strasburger, H. J., Ayata, P., Chen, X., Nair, A., Ikegami, A., Hwang, P., Chan, A. T., Graves, S. M., Uweru, J. O., et al. (2020) · Nature · doi:10.1038/s41586-020-2777-8 · Cited by 979 · see citing works
Self-citationIntrinsic mechanisms of neuronal axon regeneration
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Epigenetic regulation of brain region-specific microglia clearance activity
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Epigenetic Regulation in Neurodegenerative Diseases
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The emerging field of epigenetics in neurodegeneration and neuroprotection
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Transcriptional Convergence of Oligodendrocyte Lineage Progenitors during Development
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PRC2 is high maintenancePreprint
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“…some neurons (von Schimmelmann et al. 2016; A Schaefer, pers. comm.), while EZH1 is rather stable in all cell types, including terminally differentiated resting cells (Shen et al. 2008), ormight even show increasedmRNA and protein expression in the postnatal brain (von Schimmelmann et al. 2016).”
BackgroundInfluentialAge-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients
Mertens, J., Herdy, J. R., Traxler, L., Schafer, S. T., Schlachetzki, J. C. M., Böhnke, L., Reid, D. A., Lee, H., Zangwill, D., Fernandes, D. P., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.04.004 · Cited by 240 · see citing works
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Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease
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Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis
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“Targets of PRC2 proteins are enriched for tumor suppressor genes and genes related to mental/neurodegenerative disorders [37-39], providing a link between aging, age-related DNAm modifications and age-related diseases.”
BackgroundPatel, A. J., Wan, Y., Al‐Ouran, R., Revelli, J., Cardenas, M., Oneissi, M., Liu, X., Jalali, A., Magnotti, J. F., Muzny, D. M., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1912858116 · Cited by 197 · see citing works
“Consistent with this finding, the PRC2 complex ’ s direct targets, the HOX transcription factors (35, 36), were significantly enriched only in type B (Fig.”
Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States
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“EZH2 catalyzes H3K27 methylation and functions as a transcriptional repressor in many cell types (Margueron and Reinberg, 2011), including neurons (von Schimmelmann et al., 2016).”
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Transient loss of Polycomb components induces an epigenetic cancer fate
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“PRC2 impairment in mouse striatal neurons induces progressive neurodegeneration by triggering a self-sustaining transcription derailment programme over time 60 .”
The Polycomb-Dependent Epigenome Controls β Cell Dysfunction, Dedifferentiation, and Diabetes
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Distinct Stimulatory Mechanisms Regulate the Catalytic Activity of Polycomb Repressive Complex 2
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The Role of Epigenetic Mechanisms in the Regulation of Gene Expression in the Nervous System
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Self-citationEpigenetic Modifications Associated to Neuroinflammation and Neuropathic Pain After Neural Trauma
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“Although increases of PRC2 complex may contribute to protect neurons against neurodegeneration (von Schimmelmann et al., 2016), very recently, a couple of investigations indicate that the methyltransferase EZH2 is involved in the generation and maintenance of neuropathic pain by inflammatory…”
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Histone Methylation Regulation in Neurodegenerative Disorders
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Spatial multi-omics reveals cell-type-specific nuclear compartments
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Aging biomarkers and the brain
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A lncRNA survey finds increases in neuroprotective LINC‐PINT in Parkinson’s disease substantia nigra
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“This may relate to LINC-PINT’s interaction with PRC2 (Marin-Bejar et al., 2013, 2017), which represses genes involved in cell death in general, and in neuronal cell death specifically (von Schimmelmann et al., 2016).”
BackgroundPolycomb repressive 2 complex—Molecular mechanisms of function
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JMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells
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Annotation of chromatin states in 66 complete mouse epigenomes during development
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Structure of the PRC2 complex and application to drug discovery
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Epigenetics of Huntington’s Disease
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Contribution of Neuroepigenetics to Huntington’s Disease
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The Histone H3K27 Demethylase UTX Regulates Synaptic Plasticity and Cognitive Behaviors in Mice
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The role of EZH1 and EZH2 in development and cancer
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“compared to EZH1 or EZH2 single depletion in maintaining hematopoietic stem cells, maintaining the health of hair follicles, and preventing neurodegeneration (35-39).”
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“Genes up-regulated with Mod-CAG include those upregulated in HD KI mice, allelic series M20 module, 6 and PRC2-deficiency upregulated genes 39 (Figure S6M).”
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Entanglement of Genetics and Epigenetics in Parkinson’s Disease
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Sex-specific DNA methylation differences in Alzheimer’s disease pathology
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Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival
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Altered Extracellular Vesicle miRNA Profile in Prodromal Alzheimer’s Disease
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Role of primary aging hallmarks in Alzheimer´s disease
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“Of note, H3K9ac has been shown to co-localize with H3K14ac on the previously described poised promoters harbouring H3K4me3 and H3K27me3 [209, 251, 252].”
BackgroundInfluentialEarly alteration of epigenetic-related transcription in Huntington’s disease mouse models
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Drugging histone methyltransferases in cancer
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DZNep inhibits H3K27me3 deposition and delays retinal degeneration in the rd1 mice
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“Reduced levels of PRC2 have been implicated in activation of genes that lead to neurodegeneration in mice (von Schimmelmann et al. 2016), and have been suggested to play a role in several neurodegenerative diseases (von Schimmelmann et al. 2016, and references therein).”
BackgroundPolycomb complexes redundantly maintain epidermal stem cell identity during developmentPreprint
Cohen, I., Bar, C., Liu, H., Valdés, V. J., Zhao, D., Galbo, P. M., Silva, J. M., Koseki, H., Zheng, D., & Ezhkova, E. (2021) · Genes & Development · doi:10.1101/gad.345363.120 · Cited by 41 · see citing works
“…complexes in multiple systems have shown that loss of either PRC1 or PRC2 leads to up-regulation of nonlineage genes (Calés et al. 2008; Chiacchiera et al. 2016a; Ikawa et al. 2016; von Schimmelmann et al. 2016; Yakushiji-Kaminat-sui et al. 2016; Vidal and Starowicz 2017; Jadhav et al. 2019).”
The chromatin landscape of neuronal plasticity
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Sex Differences in the Epigenome: A Cause or Consequence of Sexual Differentiation of the Brain?
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How Polycomb‐Mediated Cell Memory Deals With a Changing Environment
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Epigenetic regulation in Huntington's disease
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The Polycomb group protein MEDEA controls cell proliferation and embryonic patterning in Arabidopsis
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EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain
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The Expanding Toolkit of Translating Ribosome Affinity Purification
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“These might be particularly informative for mutations in RNA binding proteins (Galloway et al., 2014; Tan et al., 2016) or transcriptional regulators (Rannals et al., 2016; von Schimmelmann et al., 2016), where a robust response might be expected in mRNA.”
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“…is expressed at high levels in neural stem cells, and its expression decreases during differentiation into neurons and astrocytes, but not oligodendrocytes (Sher et al., 2008); Ezh2 overexpression in astrocytes promotes de-differentiation towards a neural stem cell-like state (Sher et al., 2011).”
BackgroundNeural cell state shifts and fate loss in ageing and age-related diseases
Traxler, L., Lucciola, R., Herdy, J. R., Jones, J. R., Mertens, J., & Gage, F. H. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00815-0 · Cited by 34 · see citing works
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“In mature neurons, a recent study has shown that EZH1/ EZH2 and H3K27me3 function to protect neurons from degeneration [38].”
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“The global depletion of H3K27me3 in postmitotic neurons takes months to appear after deletion of EZH1/2 [12] revealing that this histone modification is remarkably stable across the bulk of the genome.”
BackgroundInfluentialUppala, S. N., Tryphena, K. P., Naren, P., Srivastava, S., Singh, S. B., & Khatri, D. K. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111826 · Cited by 32 · see citing works
Chromatin regulation in complex brain disorders
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Long somatic DNA-repeat expansion drives neurodegeneration in Huntington diseasePreprint
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Wilm’s tumor 1 promotes memory flexibility
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Polycomb Repressive Complex(es) and Their Role in Adult Stem Cells
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Polycomb Repressive Complex 2: Emerging Roles in the Central Nervous System
Liu, P., Xu, Y., Teng, Z., & Liu, C. (2017) · The Neuroscientist · doi:10.1177/1073858417747839 · Cited by 27 · see citing works
KDM6B cooperates with Tau and regulates synaptic plasticity and cognition via inducing VGLUT1/2
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“PRC2 deficiency of Ezh1 and Ezh2 in MSN neurons resulted in progressive fatal neurodegeneration, reduction of the number of striatal neurons and impaired motor performance with concurrent upregulation of non-MSN-expressed genes and downregulation of MSNspecific genes (105).”
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“Nonetheless, evidence indicate that EZH1 is required for synaptic development of cultured mouse hippocampal neurons 35 and to protect neurons from degeneration upon EZH2 deletion 34 .”
BackgroundToskas, K., Salmani, B. Y., Skiteva, O., Pasławski, W., Gillberg, L., Skara, V., Antoniou, E., Södersten, E., Svenningsson, P., Chergui, K., et al. (2022) · Science Advances · doi:10.1126/sciadv.abo1543 · Cited by 24 · see citing works
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“Moreover, expression changes of transcription factors, which are normally suppressed in MSNs, were observed, accompanied by progressive and fatal neurodegeneration [69].”
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Brulé, B., Alcalá‐Vida, R., Penaud, N., Scuto, J., Mounier, C., Séguin, J., Khodaverdian, S. V., Cosquer, B., Birmelé, É., Gras, S. L., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56722-z · Cited by 22 · see citing works
“To test the hypothesis, we carried out kmeans clustering analysis using striatal H3K4me3 and H3K27me3 ChIPseq data, which allowed the identi fi cation of bivalent cluster strongly enriched in PRC1/PRC2-regulated developmental genes, including Onecut1 , Pax6 and Runx2 (Fig.”
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“Moreover, the significance of PRC2 in adult neurons was reported, showing the critical role of PRC2-dependent transcriptional changes on progressive and fatal neurodegeneration in mice.(17) We therefore assessed whether the most functional DNA aptamer MS3 may discriminate the endogenous mutant and normal huntingtins e…”
BackgroundDiverse gene regulatory mechanisms mediated by Polycomb group proteins during neural development
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del Blanco, B., Niñerola, S., Martín-González, A. M., Paraíso-Luna, J., Kim, M., Muñoz-Viana, R., Racovac, C., Sanchez-Mut, J., Ruan, Y.-J., & Barco, Á. (2024) · Nature Communications · doi:10.1038/s41467-024-45773-3 · Cited by 17 · see citing works
“Supporting this view, the elimination of PRC2 in postmitotic neurons, similar to Kdm1a, triggers the expression of nonneuronal genes 42 .”
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“An example being neurons that undergo an intense maturation period in the post-natal to adult period, during which time EZH2 and EED are down-regulated, and EZH1 levels remain unchanged [102].”
BackgroundThe role of Twist1 in mutant huntingtin–induced transcriptional alterations and neurotoxicity
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“In addition, a recent study has shown that inhibition of the histone H3 Lys-27 methyltransferase complex PRC2 in neurons in mice causes up-regulation of PRC2 target genes encoding transcription factors, including Twist1, and leads to neurodegeneration (76), suggesting that PRC2 inhibition may be involved in the up-reg…”
BackgroundEstablishing and maintaining Hox profiles during spinal cord development
Miller, A., & Dasen, J. S. (2023) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2023.03.014 · Cited by 20 · see citing works
PRC1 sustains the integrity of neural fate in the absence of PRC2 function
Sawai, A., Pfennig, S., Bulajić, M., Miller, A., Khodadadi‐Jamayran, A., Mazzoni, E. O., & Dasen, J. S. (2022) · eLife · doi:10.7554/elife.72769 · Cited by 20 · see citing works
“…the temporal 397 transition from neurogenesis to gliogenesis, maintenance of adult neural stem cell fates, and 398 restriction of gene expression in mature neurons (Di Meglio et al., 2013; Fasano et al., 2009; 399 Hirabayashi et al., 2009; Molofsky et al., 2003; von Schimmelmann et al., 2016).”
BackgroundDestain, H., Prahlad, M., & Kratsios, P. (2023) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2023.07.001 · Cited by 18 · see citing works
Pletenev, I. A., Bazarevich, M., Zagirova, D., Kononkova, A. D., Cherkasov, A. V., Efimova, O., Tiukacheva, E. A., Morozov, K. V., Ulianov, K. A., Komkov, D., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae271 · Cited by 18 · see citing works
- Authors
- von Schimmelmann, M., Feinberg, P. A., Sullivan, J. M., Ku, S. M., Badimon, A., Duff, M. K., Wang, Z., Lachmann, A., Dewell, S., Ma'ayan, A., Han, M.-H., Tarakhovsky, A., & Schaefer, A.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Rockefeller University (US)
- Corresponding author
- Schaefer, Anne
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2016-08-15
- Volume
- 19
- Issue
- 10
- Pages
- 1321-1330
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC5088783
- OpenAlex
- W2512539438
- Semantic Scholar
- 646305f58c2b8331cf493f04ddf728cf29e6b59c
- Cited by
- 225
- References
- 78
- Citations by year
- 2026: 22 · 2025: 23 · 2024: 25 · 2023: 25 · 2022: 20 · 2021: 27 · 2020: 18 · 2019: 22 · 2018: 22 · 2017: 19 · 2016: 2
- FWCI
- 11.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01AA022445)
- National Institute on Aging (T32AG049688)
- National Heart, Lung, and Blood Institute (U54HL127624)
- National Institute of Mental Health (F31MH108326, R21MH112081, P50MH096890, R01MH092306, DP2MH100012, T32MH096678)
- National Cancer Institute (U54CA189201)
- National Institute of General Medical Sciences (R01GM112811, R01GM098316)
- National Institute of Neurological Disorders and Stroke (R01NS091574)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- polycomb repressive complex 2, neurodegeneration, striatum, epigenetic silencing, neuronal specification, transcriptional repression
- MeSH terms
- Animals, Cell Survival, Female, Male, Nerve Degeneration, Neurons, Histone-Lysine N-Methyltransferase, Down-Regulation, Cell Death, Mice, Knockout, Neurodegenerative Diseases, Gene Silencing, Mice, Polycomb Repressive Complex 2
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