RCCD1 promotes breast carcinogenesis through regulating hypoxia-associated mitochondrial homeostasis.

Regulator of chromosome condensation domain-containing protein 1 (RCCD1), previously reported as a partner of histone H3K36 demethylase KDM8 involved in chromosome segregation, has been identified as a potential driver for breast cancer in a recent transcriptome-wide association study. We report here that, unexpectedly, RCCD1 is also localized in mitochondria. We show that RCCD1 resides in the mitochondrial matrix, where it interacts with the mitochondrial contact site/cristae organizing system (MICOS) and mitochondrial DNA (mtDNA) to regulate mtDNA transcription, oxidative phosphorylation, and the production of reactive oxygen species. Interestingly, RCCD1 is upregulated under hypoxic conditions, leading to decreased generation of reactive oxygen species and alleviated apoptosis favoring cancer cell survival. We show that RCCD1 promotes breast cancer cell proliferation in vitro and accelerates breast tumor growth in vivo. Indeed, RCCD1 is overexpressed in breast carcinomas, and its level of expression is associated with aggressive breast cancer phenotypes and poor patient survival. Our study reveals an additional dimension of RCCD1 functionality in regulating mitochondrial homeostasis, whose dysregulation inflicts pathologic states such as breast cancer.

PD-L1-mediated immune evasion in triple-negative breast cancer is linked to the loss of ZNF652.

The intrinsic regulation of programmed death ligand-1 (PD-L1) expression remains unclear. Here, we report that zinc-finger protein 652 (ZNF652) is a potent transcription repressor of PD-L1. ZNF652 frequently experiences loss of heterozygosity (LOH) in various cancers. Higher LOH rate and lack of estrogen-inducible transcription lead to suppressed expression of ZNF652 in triple-negative breast cancer (TNBC). Mechanistically, ZNF652 is physically associated with the NuRD transcription co-repressor complex to repress a cohort of genes, including PD-L1. Overexpression of ZNF652 inhibits PD-L1 transcription, whereas depletion of ZNF652 upregulates PD-L1. Loss of ZNF652 in TNBC unleashes PD-L1-mediated immune evasion both in vitro and in vivo. Significantly, ZNF652 expression is progressively lost during breast cancer progression, and a low ZNF652 level is correlated with elevated PD-L1 expression, less infiltrated CD8+ T cells, and poor prognosis in TNBC. Our study provides insights into PD-L1 regulation and supports the pursuit of ZNF652 as a potential biomarker and drug target for breast cancer immunotherapy.

NFIB facilitates replication licensing by acting as a genome organizer.

The chromatin-based rule governing the selection and activation of replication origins in metazoans remains to be investigated. Here we report that NFIB, a member of Nuclear Factor I (NFI) family that was initially purified in host cells to promote adenoviral DNA replication but has since mainly been investigated in transcription regulation, is physically associated with the pre-replication complex (pre-RC) in mammalian cells. Genomic analyses reveal that NFIB facilitates the assembly of the pre-RC by increasing chromatin accessibility. Nucleosome binding and single-molecule magnetic tweezers shows that NFIB binds to and opens up nucleosomes. Transmission electron microscopy indicates that NFIB promotes nucleosome eviction on parental chromatin. NFIB deficiency leads to alterations of chromosome contacts/compartments in both G1 and S phase and affects the firing of a subset of origins at early-replication domains. Significantly, cancer-associated NFIB overexpression provokes gene duplication and genomic alterations recapitulating the genetic aberrance in clinical breast cancer and empowering cancer cells to dynamically evolve growth advantage and drug resistance. Together, these results point a role for NFIB in facilitating replication licensing by acting as a genome organizer, shedding new lights on the biological function of NFIB and on the replication origin selection in eukaryotes.

Intracellular galectin-3 is a lipopolysaccharide sensor that promotes glycolysis through mTORC1 activation.

How the carbohydrate binding protein galectin-3 might act as a diabetogenic and tumorogenic factor remains to be investigated. Here we report that intracellular galectin-3 interacts with Rag GTPases and Ragulator on lysosomes. We show that galectin-3 senses lipopolysaccharide (LPS) to facilitate the interaction of Rag GTPases and Ragulator, leading to the activation of mTORC1. We find that the lipopolysaccharide/galectin-3-Rag GTPases/Ragulator-mTORC1 axis regulates a cohort of genes including GLUT1, and HK2, and PKM2 that are critically involved in glucose uptake and glycolysis. Indeed, galectin-3 deficiency severely compromises LPS-promoted glycolysis. Importantly, the expression of HK2 is significantly reduced in diabetes patients. In multiple types of cancer including hepatocellular carcinoma (HCC), galectin-3 is highly expressed, and its level of expression is positively correlated with that of HK2 and PKM2 and negatively correlated with the prognosis of HCC patients. Our study unravels that galectin-3 is a sensor of LPS, an important modulator of the mTORC1 signaling, and a critical regulator of glucose metabolism.

JADE2 Is Essential for Hippocampal Synaptic Plasticity and Cognitive Functions in Mice.

BACKGROUND: Impairment of synaptic plasticity is closely correlated with a range of pathological conditions, such as cognitive deficits. However, how synaptic efficacy is regulated remains incompletely understood. Here, we report that the epigenetic factor JADE2 was indispensable for the maintenance of hippocampal synaptic plasticity and cognitive functions in mice. METHODS: We used the Morris water maze and the fear conditioning test to examine learning-related behaviors. In addition, Western blotting, viral-mediated JADE2 manipulations, RNA sequencing, and electrophysiological recordings were used to address our questions. RESULTS: JADE2 expression is increased upon enhanced neuronal activity in vitro and in vivo. Knockdown or genetic deletion of Jade2 in hippocampal CA1 results in impaired structural and functional synaptic plasticity, leading to memory impairment, whereas overexpression of JADE2 in CA1 neurons facilitates hippocampal-dependent learning and memory. Mechanistically, our data show that JADE2 modulates synaptic functions mainly by transcriptional activation of cytoskeletal regulator Rac1, and this activity is dependent on its interaction with histone acetyltransferase HBO1. Finally, we demonstrate that restoring RAC1 expression in Jade2 knockout mice could rescue the deficits in synaptic plasticity and learning-related behaviors. CONCLUSIONS: Our findings reveal that JADE2 plays a critical role in regulating synaptic plasticity and memory formation, suggesting that activity-dependent epigenetic regulation is an important molecular mechanism in controlling synaptic plasticity.

LSD1 is required for euchromatic origin firing and replication timing.

The chromatin-based rule governing the selection and activation of replication origins remains to be elucidated. It is believed that DNA replication initiates from open chromatin domains; thus, replication origins reside in open and active chromatin. However, we report here that lysine-specific demethylase 1 (LSD1), which biochemically catalyzes H3K4me1/2 demethylation favoring chromatin condensation, interacts with the DNA replication machinery in human cells. We find that LSD1 level peaks in early S phase, when it is required for DNA replication by facilitating origin firing in euchromatic regions. Indeed, euchromatic zones enriched in H3K4me2 are the preferred sites for the pre-replicative complex (pre-RC) binding. Remarkably, LSD1 deficiency leads to a genome-wide switch of replication from early to late. We show that LSD1-engaged DNA replication is mechanistically linked to the loading of TopBP1-Interacting Checkpoint and Replication Regulator (TICRR) onto the pre-RC and subsequent recruitment of CDC45 during origin firing. Together, these results reveal an unexpected role for LSD1 in euchromatic origin firing and replication timing, highlighting the importance of epigenetic regulation in the activation of replication origins. As selective inhibitors of LSD1 are being exploited as potential cancer therapeutics, our study supports the importance of leveraging an appropriate level of LSD1 to curb the side effects of anti-LSD1 therapy.

BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer.

BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2 As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex-restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.

The existence of a nonclassical TCA cycle in the nucleus that wires the metabolic-epigenetic circuitry.

The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid (TCA) cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus. We report here the identification of a nonclassical TCA cycle in the nucleus (nTCA cycle). We found that all the TCA cycle-associated enzymes including citrate synthase (CS), aconitase 2 (ACO2), isocitrate dehydrogenase 3 (IDH3), oxoglutarate dehydrogenase (OGDH), succinyl-CoA synthetase (SCS), fumarate hydratase (FH), and malate dehydrogenase 2 (MDH2), except for succinate dehydrogenase (SDH), a component of electron transport chain for generating ATP, exist in the nucleus. We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria. We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates, not for energy production. We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation. Together, our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.

SNP rs4971059 predisposes to breast carcinogenesis and chemoresistance via TRIM46-mediated HDAC1 degradation.

Identification of the driving force behind malignant transformation holds the promise to combat the relapse and therapeutic resistance of cancer. We report here that the single nucleotide polymorphism (SNP) rs4971059, one of 65 new breast cancer risk loci identified in a recent genome-wide association study (GWAS), functions as an active enhancer of TRIM46 expression. Recreating the G-to-A polymorphic switch caused by the SNP via CRISPR/Cas9-mediated homologous recombination leads to an overt upregulation of TRIM46. We find that TRIM46 is a ubiquitin ligase that targets histone deacetylase HDAC1 for ubiquitination and degradation and that the TRIM46-HDAC1 axis regulates a panel of genes, including ones critically involved in DNA replication and repair. Consequently, TRIM46 promotes breast cancer cell proliferation and chemoresistance in vitro and accelerates tumor growth in vivo. Moreover, TRIM46 is frequently overexpressed in breast carcinomas, and its expression is correlated with lower HDAC1 expression, higher histological grades, and worse prognosis of the patients. Together, our study links SNP rs4971059 to replication and to breast carcinogenesis and chemoresistance and support the pursuit of TRIM46 as a potential target for breast cancer intervention.

SCFJFK is functionally linked to obesity and metabolic syndrome.

Dysregulation of lipid metabolism could lead to the development of metabolic disorders. We report here that the F-box protein JFK promotes excessive lipid accumulation in adipose tissue and contributes to the development of metabolic syndrome. JFK transgenic mice develop spontaneous obesity, accompanied by dyslipidemia, hyperglycemia, and insulin resistance, phenotypes that are further exacerbated under high-fat diets. In contrast, Jfk knockout mice are lean and resistant to diet-induced metabolic malfunctions. Liver-specific reconstitution of JFK expression in Jfk knockout mice leads to hepatic lipid accumulation resembling human hepatic steatosis and nonalcoholic fatty liver disease. We show that JFK interacts with and destabilizes ING5 through assembly of the SCF complex. Integrative transcriptomic and genomic analysis reveals that the SCFJFK -ING5 axis interferes with AMPK activity and fatty acid ß-oxidation, leading to the suppression of hepatic lipid catabolism. Significantly, JFK is upregulated and AMPKα1 is down-regulated in liver tissues from NAFLD patients. These results reveal that SCFJFK is a bona fide E3 ligase for ING5 and link the SCFJFK -ING5 axis to the development of obesity and metabolic syndrome.

UHRF2 commissions the completion of DNA demethylation through allosteric activation by 5hmC and K33-linked ubiquitination of XRCC1.

The transition of oxidized 5-methylcytosine (5mC) intermediates into the base excision repair (BER) pipeline to complete DNA demethylation remains enigmatic. We report here that UHRF2, the only paralog of UHRF1 in mammals that fails to rescue Uhrf1-/- phenotype, is physically and functionally associated with BER complex. We show that UHRF2 is allosterically activated by 5-hydroxymethylcytosine (5hmC) and acts as a ubiquitin E3 ligase to catalyze K33-linked polyubiquitination of XRCC1. This nonproteolytic action stimulates XRCC1's interaction with the ubiquitin binding domain-bearing RAD23B, leading to the incorporation of TDG into BER complex. Integrative epigenomic analysis in mouse embryonic stem cells reveals that Uhrf2-fostered TDG-RAD23B-BER complex is functionally linked to the completion of DNA demethylation at active promoters and that Uhrf2 ablation impedes DNA demethylation on latent enhancers that undergo poised-to-active transition during neuronal commitment. Together, these observations highlight an essentiality of 5hmC-switched UHRF2 E3 ligase activity in commissioning the accomplishment of active DNA demethylation.

TRPS1 drives heterochromatic origin refiring and cancer genome evolution.

Exploitation of naturally occurring genetic mutations could empower the discovery of novel aspects of established cancer genes. We report here that TRPS1, a gene linked to the tricho-rhino-phalangeal syndrome (TRPS) and recently identified as a potential breast cancer driver, promotes breast carcinogenesis through regulating replication. Epigenomic decomposition of TRPS1 landscape reveals nearly half of H3K9me3-marked heterochromatic origins are occupied by TRPS1, where it encourages the chromatin loading of APC/C, resulting in uncontrolled origin refiring. TRPS1 binds to the genome through its atypical H3K9me3 reading via GATA and IKAROS domains, while TRPS-related mutations affect its chromatin binding, replication boosting, and tumorigenicity. Concordantly, overexpression of wild-type but not TRPS-associated mutants of TRPS1 is sufficient to drive cancer genome amplifications, which experience an extrachromosomal route and dynamically evolve to confer therapeutic resistance. Together, these results uncover a critical function of TRPS1 in driving heterochromatin origin firing and breast cancer genome evolution.

Circadian Rhythm Is Disrupted by ZNF704 in Breast Carcinogenesis.

Copy number gain in chromosome 8q21 is frequently detected in breast cancer, yet the oncogenic potential underlying this amplicon in breast carcinogenesis remains to be delineated. We report here that ZNF704, a gene mapped to 8q21, is recurrently amplified in various malignancies including breast cancer. ZNF704 acted as a transcriptional repressor and interacted with the transcriptional corepressor SIN3A complex. Genome-wide interrogation of transcriptional targets revealed that the ZNF704/SIN3A complex represses a panel of genes including PER2 that are critically involved in the function of the circadian clock. Overexpression of ZNF704 prolonged the period and dampened the amplitude of the circadian clock. ZNF704 promoted the proliferation and invasion of breast cancer cells in vitro and accelerated the growth and metastasis of breast cancer in vivo. Consistently, the level of ZNF704 expression inversely correlated with that of PER2 in breast carcinomas, and high level of ZNF704 correlated with advanced histologic grades, lymph node positivity, and poor prognosis of patients with breast cancer, especially those with HER2+ and basal-like subtypes. These results indicate that ZNF704 is an important regulator of the circadian clock and a potential driver for breast carcinogenesis. SIGNIFICANCE: This study indicates that ZNF704 could be a potential oncogenic factor, disrupting circadian rhythm of breast cancer cells and contributing to breast carcinogenesis.

Global crotonylome reveals CDYL-regulated RPA1 crotonylation in homologous recombination-mediated DNA repair.

Previously, we reported that chromodomain Y-like (CDYL) acts as a crotonyl-coenzyme A hydratase and negatively regulates histone crotonylation (Kcr). However, the global CDYL-regulated crotonylome remains unclear. Here, we report a large-scale proteomics analysis for protein Kcr. We identify 14,311 Kcr sites across 3734 proteins in HeLa cells, providing by far the largest crotonylome dataset. We show that depletion of CDYL alters crotonylome landscape affecting diverse cellular pathways. Specifically, CDYL negatively regulated Kcr of RPA1, and mutation of the Kcr sites of RPA1 impaired its interaction with single-stranded DNA and/or with components of resection machinery, supporting a key role of RPA1 Kcr in homologous recombination DNA repair. Together, our study indicates that protein crotonylation has important implication in various pathophysiological processes.

USP11 acts as a histone deubiquitinase functioning in chromatin reorganization during DNA repair.

How chromatin dynamics is regulated to ensure efficient DNA repair remains to be understood. Here, we report that the ubiquitin-specific protease USP11 acts as a histone deubiquitinase to catalyze H2AK119 and H2BK120 deubiquitination. We showed that USP11 is physically associated with the chromatin remodeling NuRD complex and functionally involved in DNA repair process. We demonstrated that USP11-mediated histone deubiquitination and NuRD-associated histone deacetylation coordinate to allow timely termination of DNA repair and reorganization of the chromatin structure. As such, USP11 is involved in chromatin condensation, genomic stability, and cell survival. Together, these observations indicate that USP11 is a chromatin modifier critically involved in DNA damage response and the maintenance of genomic stability.

Chromodomain Y-like Protein-Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors.

BACKGROUND: Major depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process. METHODS: We used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification. RESULTS: The results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress-induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter. CONCLUSIONS: Our results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.

Imbalance of the reciprocally inhibitory loop between the ubiquitin-specific protease USP43 and EGFR/PI3K/AKT drives breast carcinogenesis.

Hyperactivation of EGFR/PI3K/AKT is a prominent feature of various human cancers. Thus, understanding how this molecular cascade is balanced is of great importance. We report here that the ubiquitin-specific protease USP43 is physically associated with the chromatin remodeling NuRD complex and catalyzes H2BK120 deubiquitination. Functionally this coordinates the NuRD complex to repress a cohort of genes, including EGFR, which are critically involved in cell proliferation and carcinogenesis. We show that USP43 strongly suppresses the growth and metastasis of breast cancer in vivo. Interestingly, USP43 also exists in the cytoplasm, where it is phosphorylated by AKT, enabling its binding to the 14-3-3ß/ε heterodimer and sequestration in the cytoplasm. Significantly, hyperactivation of EGFR/PI3K/AKT in breast cancer is associated with the cytoplasmic retention of USP43 and thus, the inhibition of its transcriptional regulatory function. Moreover, cancer-associated mutations of USP43 affect its subcellular localization and/or epigenetic regulatory functions. Nuclear USP43 is significantly reduced in breast carcinomas and is associated with EGFR accumulation and AKT hyperactivation. A low level of nuclear USP43 correlates with higher histologic grades and poor prognosis. Our study identifies USP43 to be an H2BK120 deubiquitinase and a potential tumor suppressor and reveals a reciprocally inhibitory loop between USP43 and EGFR/PI3K/AKT, whose imbalance drives breast carcinogenesis.

Identification of a 35S U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complex intermediate in spliceosome assembly.

The de novo assembly and post-splicing reassembly of the U4/U6.U5 tri-snRNP remain to be investigated. We report here that ZIP, a protein containing a CCCH-type zinc finger and a G-patch domain, as characterized by us previously, regulates pre-mRNA splicing independent of RNA binding. We found that ZIP physically associates with the U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP). Remarkably, the ZIP-containing tri-snRNP, which has a sedimentation coefficient of ∼35S, is a tri-snRNP that has not been described previously. We also found that the 35S tri-snRNP contains hPrp24, indicative of a state in which the U4/U6 di-snRNP is integrating with the U5 snRNP. We found that the 35S tri-snRNP is enriched in the Cajal body, indicating that it is an assembly intermediate during 25S tri-snRNP maturation. We showed that the 35S tri-snRNP also contains hPrp43, in which ATPase/RNA helicase activities are stimulated by ZIP. Our study identified, for the first time, a tri-snRNP intermediate, shedding new light on the de novo assembly and recycling of the U4/U6.U5 tri-snRNP.

ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin.

EGFR is required for animal development, and dysregulation of EGFR is critically implicated in malignant transformation. However, the molecular mechanism underlying the regulation of EGFR expression remains poorly explored. Here we report that the zinc-finger protein ZNF516 is a transcription repressor. ZNF516 is physically associated with the CtBP/LSD1/CoREST complex and transcriptionally represses a cohort of genes including EGFR that are critically involved in cell proliferation and motility. We demonstrate that the ZNF516-CtBP/LSD1/CoREST complex inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo. Significantly, low expression of ZNF516 is positively associated with advanced pathological staging and poor survival of breast carcinomas. Our data indicate that ZNF516 is a transcription repressor and a potential suppressor of EGFR, adding to the understanding of EGFR-related breast carcinogenesis and supporting the pursuit of ZNF516 as a potential therapeutic target for breast cancer. EGFR is a well-known oncogene; however, the mechanisms regulating its expression are still unclear. Here, analysing genome-wide chromatin associations, the authors show that in breast cancer cells ZNF516 represses EGFR transcription through the interaction with the CtBP/LSD1/CoREST complex.

CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression.

Impairment of intrinsic plasticity is involved in a range of neurological disorders such as epilepsy. However, how intrinsic excitability is regulated is still not fully understood. Here we report that the epigenetic factor Chromodomain Y-like (CDYL) protein is a critical regulator of the initiation and maintenance of intrinsic neuroplasticity by regulating voltage-gated ion channels in mouse brains. CDYL binds to a regulatory element in the intron region of SCN8A and mainly recruits H3K27me3 activity for transcriptional repression of the gene. Knockdown of CDYL in hippocampal neurons results in augmented Nav1.6 currents, lower neuronal threshold, and increased seizure susceptibility, whereas transgenic mice over-expressing CDYL exhibit higher neuronal threshold and are less prone to epileptogenesis. Finally, examination of human brain tissues reveals decreased CDYL and increased SCN8A in the temporal lobe epilepsy group. Together, our findings indicate CDYL is a critical player for experience-dependent gene regulation in controlling intrinsic excitability.Alterations in intrinsic plasticity are important in epilepsy. Here the authors show that the epigenetic factor CDYL regulates the gene expression of the voltage gated sodium channel, Nav1.6, which contributes to seizures in a rat model of epilepsy.