Cell identity is determined during differentiation by the coordinated actions of chromatin regulatory factors, which serve to establish the accessibility of gene regulatory elements that control the transcription of cell-type specific genes. Histone proteins play a key role in determining the architecture of chromatin, and specific post-translational modifications of the histones are tightly associated with the transcriptional state of a given locus or gene (Hyun et al., 2017). Among these modifications, histone methylation occurs on lysine and arginine residues of specific histones, and has roles in both gene activation and repression (Jambhekar et al., 2019), and acts to alter gene transcription by recruiting the site-specific binding of effector proteins that carry out specialized functions (Daniel et al., 2005). H3K27me3 is a repressive histone modification that is best known for its role during cell-fate determination (van Mierlo et al., 2019). H3K27 methylation is deposited by the Polycomb repressive complex 2 (PRC2) lysine methyltransferases EZH1 and EZH2 (O’Carroll et al., 2001; Voncken et al., 2003). H3K27me3 can be enzymatically removed by the H3K27-specific lysine demethylases KDM6A (UTX) and KDM6B (JMJD3) (Swigut and Wysocka, 2007). In mice, null mutations in Ezh2 result in early embryonic lethality (O’Carroll et al., 2001), Kdm6a knockouts show severely impaired mid-gestational development (Welstead et al., 2012), and Kdm6b knockouts die at birth (Burgold et al., 2012) suggesting the physiological importance of H3K27me3 regulation for mammalian embryonic development.

Neurons are born very early in their overall lifespan, and they undergo significant transcriptional and functional changes during the postmitotic stages of their developmental maturation. The enzymes that write and erase H3K27me3 remain expressed in neurons both during postnatal stages of development and in the adult brain (Wijayatunge et al., 2014; Wijayatunge et al., 2018), suggesting that they have functions beyond fate determination that remain to be understood. Conditional deletion of both Ezh1 and Ezh2 in neurons of the adult mouse causes a slow global loss of H3K27me3 as well as progressive neurodegeneration and death showing the importance of these enzymes in adult neurons (von Schimmelmann et al., 2016). One possibility is that H3K27me3 is required for fate maintenance. For example, deleting EED in developing postmitotic dopamine or serotonin neurons in vivo leads not only to the loss of H3K27me3 but also to reduced expression of the enzymes that define the transmitter phenotype of these neuromodulatory neurons (Toskas et al., 2022). Other studies suggest that H3K27me3 might be required in terminally differentiated neurons to persistently repress genes that have the potential to drive trans-differentiation to alternate cell fates (Ferrai et al., 2017; von Schimmelmann et al., 2016).

The global depletion of H3K27me3 in postmitotic neurons takes months to appear after the deletion of EZH1/2 (von Schimmelmann et al., 2016) revealing that this histone modification is remarkably stable across the bulk of the genome. Although histone replacement is a major mechanism of H3K27me3 removal in dividing cells (Shpargel et al., 2014), histone turnover is very slow in postmitotic neurons (Maze et al., 2015). Interestingly, H3K27-selective lysine demethylases are widely expressed in the adult brain suggesting that these enzymes may have a particularly important role in the local regulation of histone methylation patterns in postmitotic cells (Swahari and West, 2019). Both Kdm6a and Kdm6b are expressed in neurons over the course of brain development, though only Kdm6b shows enhanced expression following exposure of cells to neuronal differentiation cues (Burgold et al., 2008; De Santa et al., 2009; Jepsen et al., 2007; Wijayatunge et al., 2018). Germline knockout of Kdm6b does not impair the gross architecture of the embryonic brain, but it does result in perinatal lethality caused by disruption of the functional maturation of a respiratory circuit that is required for proper breathing after birth (Burgold et al., 2012). This phenotype arises as a result of the lost demethylase function of Kdm6b, because survival cannot be rescued by transgenic expression of a demethylase-dead Kdm6b in the knockout mice (Burgold et al., 2012). These data are important because they suggest that demethylation mediated by Kdm6b is essential for the proper function of postmitotic neurons. Chromatin regulators are one of the major classes of genes associated with autism spectrum disorder (ASD) and notably KDM6B has been identified as a high-confidence ASD risk gene in humans (Satterstrom et al., 2020). Kdm6b haploinsufficiency in mice is associated with ASD-like impairments in sociability suggesting its importance for proper social network function in the adult brain (Gao et al., 2022), however, the underlying chromatin and transcriptional mechanisms of these Kdm6b mutation phenotypes remain to be elucidated.

We use CGNs to model neurodevelopment because they comprise more than 99% of all neurons (Consalez et al., 2021) and 85% of cells (Altman and Bayer, 1997) in the cerebellum, enabling the in vivo comparison of chromatin across CGN developmental states with limited contamination from other cell types. When purified and placed in ex vivo culture, CGN progenitors coordinately exit the cell cycle, minimizing heterogeneity of cell developmental stage across the population (Fogarty et al., 2007). In both preparations, gene transcription programs change over time coincident with changes in CGN biology (e.g. proliferation, migration, synapse formation, and synapse maturation Frank et al., 2015; Sathyanesan et al., 2019). We previously showed that loss of Kdm6a/b had no effect on postnatal morphogenesis of the cerebellum, demonstrating these enzymes are not required in vivo for the regulation of CGN progenitor proliferation (Wijayatunge et al., 2018). However, knockdown of Kdm6b in cultured CGNs impaired the developmental induction of genes during the period of postmitotic neuronal maturation (Wijayatunge et al., 2018). Based on these data, we hypothesized that H3K27me3 may serve as a temporal gatekeeper of these maturation genes, delaying their activation beyond the immediate period of terminal differentiation to the neuronal fate.

Here to directly test the hypothesis that H3K27me3 regulation serves as a mechanism of neuronal maturation we determined the role of H3K27me3 dynamics in changing programs of gene transcription in postmitotic CGNs. We used ChIP-seq and a CUT&RUN time course study to identify the genomic location and timing of differential sites of H3K27me3 enrichment across the genome of fate-committed CGNs developing in vivo and in culture. We observed that H3K27me3 distributions continue to change even after fate-committed CGN progenitors exit the cell cycle, and that the loss of H3K27me3 at gene promoters is associated with the activation of genes induced as neurons mature. We also found a smaller subset of differential H3K27me3 peaks that occur at poised enhancers, which are dually marked by H3K27me3 and H3K4me1 and inversely correlated over time with H3K27ac enrichment. We used both genetic and pharmacological approaches to disrupt the action of H3K27me3 regulatory enzymes and show evidence of roles for both the lysine demethylase KDM6B and the lysine methyltransferase EZH2 in the induction of a postmitotic program of gene transcription that underlies functional maturation of CGNs. Taken together, our data advance our understanding of how programs of gene expression are temporally orchestrated by changing H3K27me3 distributions in the chromatin of maturing neurons.

In this study, we investigated the role of H3K27me3 turnover in postmitotic gene regulation, using the maturation of mouse CGNs as a model system. PRC2 activity has long been studied as a mechanism of early cell-fate specification in mammals through the deposition of H3K27me3 and silencing of fate-defining genes during the differentiation of embryonic stem cells (ESCs) into other cell types including neural progenitor cells (NPCs) and early neurogenesis (Mohn et al., 2008; O’Carroll et al., 2001; Pereira et al., 2010). Our study demonstrates that dynamic changes in H3K27me3 continue in postmitotic neurons at specific sites in the genome to coordinate the temporal induction of gene expression programs that underlie functional maturation. Increases in H3K27me3 occurred rapidly after cell cycle exit, whereas demethylation occurred gradually and these turnover kinetics strongly correlated with the kinetics of regulated gene expression. We identified a subset of transcriptional enhancers that show developmental regulation of H3K27me3 but observed a bias in the genomic distribution of regulated sites toward gene promoters, especially for sites of H3K27me3 demethylation. Promoters that gained H3K27me3 after cell cycle exit were enriched for genes involved in proliferation and cell-fate specification such as Atoh1 and Myc. By contrast, developmentally demethylated promoters included those for genes that confer mature function on synapses such as the NMDA receptor subunit Grin2c and the metabotropic glutamate receptor Grm4. This suggested to us that there are temporally coordinated mechanisms of enzymatic H3K27me3 turnover during CGN maturation, and that postmitotic H3K27me3 demethylation may be a key step for timing functional synaptic maturation.

Our in vivo cerebellar data show that developmental loss of H3K27me3 from gene promoters is facilitated by KDM6B, and further conditional knockout of KDM6B in CGNs impaired the expression of genes that are induced as CGNs mature. Kdm6b expression is upregulated in newborn CGNs in the inner EGL (Wijayatunge et al., 2018), and we speculate that the temporal increase in expression of this enzyme may tip the balance of H3K27me3 regulation to favor histone demethylation at specific target sites. Our evidence that genes with increased H3K27me3 in the Kdm6b-cKO mice overlap those that show developmental loss of H3K27me3 is consistent with the possibility that KDM6B functions enzymatically to demethylate histones at these gene promoters. However, chromatin regulators including KDM6B have scaffolding functions as well as enzymatic functions (Kim et al., 2013; Kim et al., 2018; Miller et al., 2010; Ohguchi et al., 2017; Xun et al., 2017), thus we attempted to use pharmacological inhibition of KDM6B to validate the role of its enzymatic activity in developing CGN gene regulation. The small molecule GSK-J4 is a relatively selective inhibitor of the KDM6 family compared with other histone demethylases, and it was previously demonstrated in primary human macrophages to block LPS-mediated histone demethylation and induction of TNFa expression with an IC₅₀ of 9 µM and no apparent toxicity up to 30 µM (Kruidenier et al., 2012). By contrast, we found 50% cytotoxicity in CGNs at a GSK-J4 concentration of just 3.1 µM and no evidence by western blot or CUT&RUN for any global or local changes in H3K27me3 when the drug was applied at the non-toxic dose of 1 µM.

Moving forward, as an alternative to pharmacological inhibition of KDM6B, genetic mutation of the JmjC domain of KDM6B offers an effective means to test its functional requirement in neuronal H3K27me3 demethylation (Nakka et al., 2022). Indeed, a prior study showed that in a BAC transgene, enzymatically dead KDM6B was unable to rescue perinatal death in KDM6B knockout mice, which is consistent with a requirement for the enzymatic function of KDM6B in the maturation of the respiratory circuit (Burgold et al., 2012). Our data now identify a set of genes induced in maturing neurons that function at synapses and require active H3K27me3 demethylation for their induction. Several of the targets of KDM6B-regulated demethylation and induction encode gene products known to play key roles in the functional maturation of synapses. These include the glutamate receptor subunit genes Grin2c and Grm4, which play important roles in cerebellar motor function and synaptic plasticity (Kadotani et al., 1996; Pekhletski et al., 1996), the GABA-A receptor delta subunit gene (Gabrd), which modulates the subcellular localization and neurosteroid sensitivity of GABA-A receptors (Vicini et al., 2002) and the neuronal pentraxin receptor gene Nptxr, which promotes the formation and stabilization of both excitatory and inhibitory synapses (Lee et al., 2017). Impaired or delayed induction of these genes in the absence of KDM6B has implications for understanding how mutations in KDM6B may lead to behavioral phenotypes in ASD via altered maturation of neural circuit function. Interestingly, mutations in another ASD-associated chromatin regulator, DNMT3A, that impair DNA methylation-dependent mechanisms of gene repression appear to be partially compensated by changes in H3K27me3 (Li et al., 2022). Future studies will be needed to address whether the modulation of H3K27me3 could function as a point of biological convergence downstream of multiple ASD-associated chromatin regulators.

Our observation that H3K27me3 removal occurs at only a subset of genes that are developmentally induced during CGN maturation raises the question of how these promoters are marked for methylation and demethylation. Through an unbiased approach, we showed that promoters that lose H3K27me3 during CGN maturation are strongly enriched for binding of the transcription factors ZIC1/2; thus, one possibility is that an interaction between KDM6B and the ZICs selects these genes for induction in maturing neurons. ZIC1/2 are strong drivers of CGN maturation (Frank et al., 2015), and mutation of these genes is associated with cerebellar disorders, showing their importance in CGN development (Blank et al., 2011; Twigg et al., 2015). ZIC1 and 2 are zinc-finger binding proteins that exhibit dynamic DNA binding properties during cerebellar maturation, and they regulate the expression of both early and late CGN maturation genes (Frank et al., 2015). Given the strong association of H3K27ac enrichment at these promoters, however, it is likely that ZIC1/2 binding is a consequence and not a cause of H3K27-demethylation at promoters. It would, therefore, be essential to measure the genome-wide enrichment patterns of KDM6B during CGN maturation, in order to identify its binding partners and direct targets. Existing literature investigating KDM6B dynamics across the epigenome is sparse owing to the lack of well-validated, commercially available KDM6B antibodies. Nevertheless, KDM6B has been shown to localize to promoters and enhancers of neurogenic genes in NSCs (Estarás et al., 2012; Park et al., 2014), and more recently to induce muscle regeneration gene Has2, by removing H3K27me3 from its promoter, to initiate muscle repair in response to injury (Nakka et al., 2022). KDM6B targeting to these specific loci might be facilitated through interactions with TFs (Dai et al., 2010; Estarás et al., 2012), and chromatin remodeling complexes (De Santa et al., 2007). For example, KDM6B has been shown to strongly associate with the ATP-dependent chromatin remodelers mSWI/SNF or BAF complex, by interacting with its subunits which in turn potentiate its activity (Narayanan et al., 2015). This interaction has been shown to play a role in neuronal development (Narayanan et al., 2015; Nguyen et al., 2018).

Interestingly, we find that maturation of CGN transcriptional programs not only depends on the loss of H3K27me3 at genes that turn on late, but also requires the addition of H3K27me3 at regions that gain this mark in newly postmitotic neurons. Using CUT&RUN in cultured CGNs, we discovered that the rapid increases in H3K27me3 that accumulate in newly postmitotic neurons are highly sensitive to inhibition of EZH2 with GSK-126. Failure to gain H3K27me3 at these sites in differentiating neurons not only prevented the developmental downregulation of CGN progenitor markers like Mycn, Jag1, and Ebf3 but also impaired the developmental induction of late genes like Gabrd, Grm4, and Grin2c. The impact of GSK-126 on the mature CGN transcriptional program, however, was not due to changes in H3K27me3 regulation at promoters of the late genes themselves. This shows that the postmitotic addition of H3K27me3 at specific genomic sites is crucial in regulating the induction of genes that turn on well after neuronal cell fate is determined.

These data raise the question of how the PRC2 complex function might indirectly regulate the activation of late gene expression programs over a period of days. One prior study that reported the consequences of knocking out EZH2 in postmitotic neuronal cultures showed that this resulted in the loss of H3K27me3 at the promoter of the Prdm13 gene and enhanced expression of this transcriptional repressor, which they suggested then led indirectly to reduced expression of its target genes in the knockout neurons (Buontempo et al., 2022). Though a similar mechanism could be at play in our cultures, Prdm13 expression and promoter H3K27me3 were unaffected by EZH2 inhibition in our DIV5 CGNs, thus we have considered alternative explanations. Notably, developmental gains in H3K27me3 during postmitotic differentiation are relatively equally split between promoters, gene bodies, and distal intergenic regions (Figure 1D). By comparing these sites of H3K27me3 regulation to other chromatin marks, we found that the majority of non-promoter peaks of H3K27me3 do not overlap enhancers. These data raise the possibility that rather than functioning to control transcriptional regulatory elements directly, H3K27me3 might contribute to gene regulation through an alternate mechanisms such as by impacting chromatin architecture. PRC2-dependent deposition of H3K27me3 has been shown in some cases to contribute to physical interactions between enhancers and their target genes by anchoring chromatin loops (Cruz-Molina et al., 2017; Kraft et al., 2022). These loops may then poise genes for enhancer activation later upon receiving a developmental stimulus. The gain of H3K27me3 in early differentiating CGNs could serve a similar function to establish such enhancer contacts with the promoters of late genes such that when KDM6B demethylates these promoters, the enhancer can permit activation. In the future, investigating dynamics in higher-order chromatin structure through low-input techniques such as HiCAR (Wei et al., 2022) might help inform how H3K27me3 dynamics contribute to gene regulation in postmitotic neurons.

H3K27me3 ChIP-seq data for P7, P14 and P60 cerebellum, WT and Kdm6b-cKO cerebellum; RNA-seq data for WT and Kdm6b-cKO cerebellum; CUT&RUN and RNA-seq data for cultured CGNs can be accessed at GEO: GSE212441. RNA-seq data for P7, P14 and P60 cerebellum and DIV0 and DIV7 CGNs, H3K27ac, ZIC1/2 ChIP-seq data and DHS-seq data for P7 and P60 cerebellum were adapted from Frank et al., 2015. H3K4me3 ChIP-seq data from P6 and P22 cerebellum were obtained and adapted from Yamada et al., 2014 and can be accessed at GEO: GSE57758. H3K4me1 ChIP-seq data from P9 cerebellum was obtained and adapted from Ramirez et al., 2022 and can be accessed at GEO: GSE183697. H3K4me3 PLAC-seq tracks were obtained from Yamada et al., 2019 and can be accessed at GEO: GSE127995. Source data files for western blots in Figure 1, 7, Figure 1—figure supplement 1 and Figure 7—figure supplement 1 are included. Primers used to perform RT-qPCR have been provided in Supplementary file 1. DESeq2-normalized counts used to generate heatmaps in the study have been provided in Supplementary file 2. Gene lists used for Gene Ontology analyses have been provided in Supplementary file 3. Processed data, DESeq2 outputs and more are provided at https://github.com/WestLabDuke/CGN_H3K27me3_Dynamics, (copy archived at West Lab at Duke, 2023).

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Author details

1. Vijyendra Ramesh

   Molecular Cancer Biology Program, Duke University, Durham, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Fang Liu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8818-6863

2. Fang Liu

   Department of Neurobiology, Duke University, Durham, United States

   Contribution

   Conceptualization, Investigation, Methodology

   Contributed equally with

   Vijyendra Ramesh

   Competing interests

   No competing interests declared

3. Melyssa S Minto

   Department of Neurobiology, Duke University, Durham, United States

   Contribution

   Formal analysis

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5438-7285

4. Urann Chan

   Department of Neurobiology, Duke University, Durham, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

5. Anne E West

   1. Molecular Cancer Biology Program, Duke University, Durham, United States
   2. Department of Neurobiology, Duke University, Durham, United States

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft, Writing - review and editing

   For correspondence

   west@neuro.duke.edu

   Competing interests

   Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0003-0846-139X

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