• 3D chromatin architecture
• Brain
• Cognition
• Engram
• Enhancer–promoter interactions
• Epidrugs
• Epigenetic editing
• Epigenome
• Synapse

• Animals
• Epigenesis, Genetic
• Humans
• Memory/physiology
• Learning/physiology
• Neuronal Plasticity
• DNA Methylation

• Animals
• Nerve Regeneration/physiology
• Axons/physiology
• Humans
• Neurogenesis/physiology
• Neurons/physiology

• ASD
• Behavior
• Gene editing
• KDM6B
• NMDA

• Animals
• Jumonji Domain-Containing Histone Demethylases/genetics
• Jumonji Domain-Containing Histone Demethylases/metabolism
• Mice, Knockout
• Synaptic Transmission/genetics
• Autism Spectrum Disorder/genetics
• Mice
• Brain/metabolism
• Neuronal Plasticity/genetics
• Behavior, Animal
• Hippocampus/metabolism
• Epigenesis, Genetic
• Male
• Synapses/metabolism

• ASD
• Gene editing
• Synaptic vesicles
• VPS50
• Vesicle acidification

• Animals
• Mice
• Behavior, Animal/physiology
• Brain/metabolism
• Mice, Knockout
• Neurons/metabolism
• Neurons/physiology
• Synapses/metabolism
• Synapses/physiology
• Synaptic Transmission
• Synaptic Vesicles/metabolism
• Vacuolar Proton-Translocating ATPases/metabolism
• Vacuolar Proton-Translocating ATPases/genetics
• Vesicular Transport Proteins/genetics
• Vesicular Transport Proteins/metabolism

• Exploración-ANID 13220203 Agencia Nacional de Investigación y Desarrollo
• R01 GM024663 NIGMS NIH HHS
• R01-EY014420 NEI NIH HHS
• Fondequip # EQM160154 Agencia Nacional de Investigación y Desarrollo
• R01-GM024663 NIGMS NIH HHS
• FONDECYT Regular # 1220480 Agencia Nacional de Investigación y Desarrollo
• UNAB DI-02-22/REG Universidad Andrés Bello
• ANID-MILENIO (NCN2023_23) Agencia Nacional de Investigación y Desarrollo
• FONDECYT Regular #1201848 Agencia Nacional de Investigación y Desarrollo
• Fondecyt Iniciación 11180540 Agencia Nacional de Investigación y Desarrollo
• PAI 77180077 Agencia Nacional de Investigación y Desarrollo
• R03 EY014420 NEI NIH HHS
• National Institute of General Medical Sciences
• National eye institute

• cancer
• cell biology
• molecular biology

• Enhancer of Zeste Homolog 2 Protein/metabolism
• Enhancer of Zeste Homolog 2 Protein/genetics
• S-Phase Kinase-Associated Proteins/metabolism
• S-Phase Kinase-Associated Proteins/genetics
• Humans
• Signal Transduction
• Cell Cycle/genetics
• Epithelial-Mesenchymal Transition/genetics
• Cyclin-Dependent Kinase Inhibitor p21/metabolism
• Cyclin-Dependent Kinase Inhibitor p21/genetics
• Cyclin-Dependent Kinase Inhibitor p57/metabolism
• Cyclin-Dependent Kinase Inhibitor p57/genetics
• Cyclin-Dependent Kinase Inhibitor p27/metabolism
• Cyclin-Dependent Kinase Inhibitor p27/genetics
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Cell Proliferation

• R01 CA213159 NCI NIH HHS
• CA213159 NIH HHS
• National Institutes of Health

• ASO - antisense oligonucleotides
• EZH2 (enhancer of zeste homolog 2)
• FMR1 reactivation
• FMR1 silencing
• FXS
• neuron differentiation

• R01 MH113874 NIMH NIH HHS
• R01 NS111990 NINDS NIH HHS

• ASD
• CRISPR/Cas9
• KMT2C
• behavior
• epigenetics

• autism spectrum disorders

• Animals
• Chick Embryo
• Humans
• Cell Differentiation/genetics
• Cell Nucleus
• Chromatin/genetics
• Methyltransferases
• Neurodevelopmental Disorders/genetics
• Neurogenesis/genetics
• Polycomb Repressive Complex 2/genetics

• R35 NS097370 NINDS NIH HHS
• P50 HD103538 NICHD NIH HHS
• RF1 MH123979 NIMH NIH HHS
• R21 HD107592 NICHD NIH HHS
• MR/S006753/1 Medical Research Council
• R01 NS119699 NINDS NIH HHS
• Wellcome Trust
• R35 NS116843 NINDS NIH HHS
• WT098051 Wellcome Trust
• U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)

• R01 GM024663 NIGMS NIH HHS
• R03 EY014420 NEI NIH HHS

• Autism spectrum disorder
• DNA methylation
• Epigenetics
• Oxytocin
• Oxytocin receptor gene
• Social experience

• Child
• Humans
• Autism Spectrum Disorder/genetics
• Epigenesis, Genetic
• Epigenome
• DNA Methylation
• Oxytocin

• P50 HD103556 NICHD NIH HHS

• MALAT1
• Polycomb Repressive Complex 2
• chromatin
• long non-coding RNA

• ANID FONDECYT Iniciacion 11200308 Agencia Nacional de Investigación y Desarrollo
• Nucleo UNAB DI-03-22/NUC Andrés Bello University

• Neural progenitor cells
• Neuronal development
• Neurons
• Post-transcriptional gene regulation
• miR-124

• 5-FU
• EZH1
• MYCN
• TYMS
• neuroblastoma

Healthy brain functioning in mammals requires a continuous fine-tuning of gene expression. Accumulating evidence over the last three decades demonstrates that epigenetic mechanisms and dynamic changes in chromatin organization are critical components during the control of gene transcription in neural cells. Recent genome-wide analyses show that the regulation of brain genes requires the contribution of both promoter and long-distance enhancer elements, which must functionally interact with upregulated gene expression in response to physiological cues. Hence, a deep comprehension of the mechanisms mediating these enhancer–promoter interactions (EPIs) is critical if we are to understand the processes associated with learning, memory and recall. Moreover, the onset and progression of several neurodegenerative diseases and neurological alterations are found to be strongly associated with changes in the components that support and/or modulate the dynamics of these EPIs. Here, we overview relevant discoveries in the field supporting the role of the chromatin organization and of specific epigenetic mechanisms during the control of gene transcription in neural cells from healthy mice subjected to the fear conditioning paradigm, a relevant model to study memory ensemble. Additionally, special consideration is dedicated to revising recent results generated by investigators working with animal models and human postmortem brain tissue to address how changes in the epigenome and chromatin architecture contribute to transcriptional dysregulation in Alzheimer’s disease, a widely studied neurodegenerative disease. We also discuss recent developments of potential new therapeutic strategies involving epigenetic editing and small chromatin-modifying molecules (or epidrugs).

• Animals
• Humans
• Mice
• Chromatin/genetics
• Alzheimer Disease/genetics
• Neurodegenerative Diseases/genetics
• Neurodegenerative Diseases/therapy
• Genome-Wide Association Study
• Epigenesis, Genetic
• Fear
• Brain
• Mammals/genetics

• Fmr1
• Fragile X Syndrome
• Reelin

Apical periodontitis (AP) is an inflammatory disease occurring following tooth infection with distinct osteolytic activity. Despite increasing evidence that sensory neurons participate in regulation of non-neuronal cells, their role in the development of AP is largely unknown. We hypothesized that trigeminal ganglia (TG) Nav1.8⁺ nociceptors regulate bone metabolism changes in response to AP. A selective ablation of nociceptive neurons in Nav1.8^Cre/Diphtheria toxin A (DTA)^Lox mouse line was used to evaluate the development and progression of AP using murine model of infection-induced AP. Ablation of Nav1.8⁺ nociceptors had earlier progression of AP with larger osteolytic lesions. Immunohistochemical and RNAscope analyses demonstrated greater number of macrophages, T-cells, osteoclast and osteoblast precursors and an increased RANKL:OPG ratio at earlier time points among Nav1.8^Cre/ DTA^Lox mice. There was an increased expression of IL-1α and IL-6 within lesions of nociceptor-ablated mice. Further, co-culture experiments demonstrated that TG neurons promoted osteoblast mineralization and inhibited osteoclastic function. The findings suggest that TG Nav1.8⁺ neurons contribute to modulation of the AP development by delaying the influx of immune cells, promoting osteoblastic differentiation, and decreasing osteoclastic activities. This newly uncovered mechanism could become a therapeutic strategy for the treatment of AP and minimize the persistence of osteolytic lesions in refractory cases.

The online version contains supplementary material available at 10.1007/s00018-022-04335-w.

• Bone
• Nav1.8
• Neurons
• Nociceptor
• Osteolytic
• Sensory

• Animals
• Astrocytes/metabolism
• Cell Culture Techniques
• Cells, Cultured
• Cytostatic Agents/pharmacology
• Deoxyuridine/analogs & derivatives
• Floxuridine/pharmacology
• Hippocampus
• Neurons/metabolism
• Rats

• Deutsche Forschungsgemeinschaft

• CBX8
• H3K27Me3
• MCC
• PRC1
• PTEN
• chromatin modifications
• mitosis

• Cell Cycle/physiology
• Cell Proliferation/physiology
• Chromatin/metabolism
• Histones/metabolism
• Humans
• Mitosis/physiology
• PTEN Phosphohydrolase/metabolism
• Phosphorylation
• Polycomb Repressive Complex 1/genetics
• Polycomb Repressive Complex 1/metabolism
• Polycomb-Group Proteins/genetics
• Polycomb-Group Proteins/metabolism

• P30 ES000260 NIEHS NIH HHS
• R01 CA213159 NCI NIH HHS
• ES000260 NIH HHS
• CA213159 NIH HHS
• National Institutes of Health

The Human Herpesviruses persist in the form of a latent infection in specialized cell types. During latency, the herpesvirus genomes associate with cellular histone proteins and the viral lytic genes assemble into transcriptionally repressive heterochromatin. Although there is divergence in the nature of heterochromatin on latent herpesvirus genomes, in general, the genomes assemble into forms of heterochromatin that can convert to euchromatin to permit gene expression and therefore reactivation. This reversible form of heterochromatin is known as facultative heterochromatin and is most commonly characterized by polycomb silencing. Polycomb silencing is prevalent on the cellular genome and plays a role in developmentally regulated and imprinted genes, as well as X chromosome inactivation. As herpesviruses initially enter the cell in an un-chromatinized state, they provide an optimal system to study how de novo facultative heterochromatin is targeted to regions of DNA and how it contributes to silencing. Here, we describe how polycomb-mediated silencing potentially assembles onto herpesvirus genomes, synergizing what is known about herpesvirus latency with facultative heterochromatin targeting to the cellular genome. A greater understanding of polycomb silencing of herpesviruses will inform on the mechanism of persistence and reactivation of these pathogenic human viruses and provide clues regarding how de novo facultative heterochromatin forms on the cellular genome.

• herpesvirus
• latency
• polycomb silencing
• virus

• Alzheimer's disease
• Nrn1
• Polycomb group proteins
• depression
• epigenetics
• neuronal maturation

• Chromatin accessibility
• Epigenetics
• Neural progenitor
• Neurodevelopment
• Radial glia
• Transcriptional regulation

• Animals
• Chromatin/chemistry
• Chromatin/metabolism
• Chromatin Assembly and Disassembly
• DNA Helicases/genetics
• DNA Helicases/metabolism
• Epigenesis, Genetic
• Histones/genetics
• Histones/metabolism
• Humans
• Neurodevelopmental Disorders/metabolism
• Neurodevelopmental Disorders/pathology
• Neurons/metabolism
• Protein Processing, Post-Translational/genetics

• 610264 Simons Foundation Autism Research Initiative (US)
• Radboud University Medical Center

Ezh2 is a catalytic subunit of the polycomb repressive complex 2 (PRC2) which mediates epigenetic gene silencing through depositing the mark histone H3 lysine 27 trimethylation (H3K27me3) at target genomic sequences. Previous studies have demonstrated that Enhancer of Zeste Homolog 2 (Ezh2) was differentially expressed during maturation of hippocampal neurons; in immature neurons, Ezh2 was abundantly expressed, whereas in mature neurons the expression Ezh2 was significantly reduced. Here, we report that Ezh2 is downregulated by microRNAs (miRs) that are expressed during the hippocampal maturation process. We show that, in mature hippocampal neurons, lethal-7 (let-7) and microRNA-124 (miR-124) are robustly expressed and can target cognate motifs at the 3′-UTR of the Ezh2 gene sequence to downregulate Ezh2 expression. Together, these data demonstrate that the PRC2 repressive activity during hippocampal maturation is controlled through a post-transcriptional mechanism that mediates Ezh2 downregulation in mature neurons.

• Ezh2 expression
• let-7 and mir-124 in hippocampus
• microRNA-mediated control

• 3' Untranslated Regions/genetics
• Animals
• Cell Line
• Down-Regulation/genetics
• Enhancer of Zeste Homolog 2 Protein/genetics
• Epigenesis, Genetic/genetics
• Female
• HEK293 Cells
• Hippocampus/physiology
• Histones/genetics
• Humans
• MicroRNAs/genetics
• Neurons/physiology
• Polycomb Repressive Complex 2/genetics
• Pregnancy
• RNA Interference/physiology
• Rats
• Rats, Sprague-Dawley

Environmentally induced epigenetic changes can lead to health problems or disease, but the mechanisms involved remain unclear. Morphine can pass through the placental barrier leading to abnormal embryo development. However, the mechanism by which morphine causes these effects and how they sometimes persist into adulthood is not well known. To unravel the morphine-induced chromatin alterations involved in aberrant embryo development, we explored the role of the H3K27me3/PRC2 repressive complex in gene expression and its transmission across cellular generations in response to morphine.

Using mouse embryonic stem cells as a model system, we found that chronic morphine treatment induces a global downregulation of the histone modification H3K27me3. Conversely, ChIP-Seq showed a remarkable increase in H3K27me3 levels at specific genomic sites, particularly promoters, disrupting selective target genes related to embryo development, cell cycle and metabolism. Through a self-regulatory mechanism, morphine downregulated the transcription of PRC2 components responsible for H3K27me3 by enriching high H3K27me3 levels at the promoter region. Downregulation of PRC2 components persisted for at least 48 h (4 cell cycles) following morphine removal, though promoter H3K27me3 levels returned to control levels.

Morphine induces targeting of the PRC2 complex to selected promoters, including those of PRC2 components, leading to characteristic changes in gene expression and a global reduction in H3K27me3. Following morphine removal, enhanced promoter H3K27me3 levels revert to normal sooner than global H3K27me3 or PRC2 component transcript levels. We suggest that H3K27me3 is involved in initiating morphine-induced changes in gene expression, but not in their maintenance.

Model of Polycomb repressive complex 2 (PRC2) and H3K27me3 alterations induced by chronic morphine exposure. Morphine induces H3K27me3 enrichment at promoters of genes encoding core members of the PRC2 complex and is associated with their transcriptional downregulation.

• Embryo
• Epigenetic
• H3K27me3
• Morphine
• Next generation sequencing
• PRC2

• epigenetic control of gene transcription
• silencing of non-neural genes in hippocampal cells

UTX, a H3K27me3 demethylase, plays an important role in mouse brain development. However, so little is known about the function of UTX in human neural differentiation and dendritic morphology. In this study, we generated UTX-null human embryonic stem cells using CRISPR/Cas9, and differentiated them into neural progenitor cells and neurons to investigate the effects of UTX loss of function on human neural development. The results showed that the number of differentiated neurons significantly reduced after loss of UTX, and that the dendritic morphology of UTX KO neurons tended to be simplified. The electrophysiological recordings showed that most of the UTX KO neurons were immature. Finally, RNA sequencing identified dozens of differentially expressed genes involved in neural differentiation and synaptic function in UTX KO neurons and our results demonstrated that UTX regulated these critical genes by resolving bivalent promoters. In summary, we establish a reference for the important role of UTX in human neural differentiation and dendritic morphology.

•

Loss of UTX in hESCs reduces their neural differentiation potential

• UTX
• bivalent promoters
• dendritic morphology
• neural differentiation

• Base Sequence
• Cell Differentiation/genetics
• Cell Line
• Cell Lineage/genetics
• Cell Self Renewal
• Dendrites/metabolism
• Electrophysiological Phenomena
• Histone Demethylases/metabolism
• Histones/metabolism
• Human Embryonic Stem Cells/cytology
• Human Embryonic Stem Cells/metabolism
• Humans
• Lysine/metabolism
• Methylation
• Neurites/metabolism
• Promoter Regions, Genetic
• Transcription, Genetic
• Up-Regulation/genetics

Placental and fetal hypoxia caused by perinatal hypoxic-ischemic events are major causes of stillbirth, neonatal morbidity, and long-term neurological sequelae among surviving neonates. Brain hypoxia and associated pathological processes such as excitotoxicity, apoptosis, necrosis, and inflammation, are associated with lasting disruptions in epigenetic control of gene expression contributing to neurological dysfunction. Recent studies have pointed to DNA (de)methylation, histone modifications, and non-coding RNAs as crucial components of hypoxic-ischemic encephalopathy (HIE). The understanding of epigenetic dysregulation in HIE is essential in the development of new clinical interventions for perinatal HIE. Here, we summarize our current understanding of epigenetic mechanisms underlying the molecular pathology of HI brain damage and its clinical implications in terms of new diagnostic, prognostic, and therapeutic tools.

• DNA methylation
• biomarker
• histone modifications
• hypoxia
• hypoxic-ischemic encephalopathy
• ischemia
• microRNAs

Hematopoietic stem cells (HSCs) exist in a dormant state and progressively lose regenerative potency as they undergo successive divisions. Why this functional decline occurs and how this information is encoded is unclear. To better understand how this information is stored, we performed RNA sequencing on HSC populations differing only in their divisional history. Comparative analysis revealed that genes upregulated with divisions are enriched for lineage genes and regulated by cell-cycle-associated transcription factors, suggesting that proliferation itself drives lineage priming. Downregulated genes are, however, associated with an HSC signature and targeted by the Polycomb Repressive Complex 2 (PRC2). The PRC2 catalytic subunits Ezh1 and Ezh2 promote and suppress the HSC state, respectively, and successive divisions cause a switch from Ezh1 to Ezh2 dominance. We propose that cell divisions drive lineage priming and Ezh2 accumulation, which represses HSC signature genes to consolidate information on divisional history into memory.

•

Divisional history is a major source of gene expression variation across HSCs

• cell heterogeneity
• divisional history
• epigenetics
• hematopoietic stem cells
• leukemia
• memory
• polycomb repressive complex

• Animals
• Cell Division/genetics
• Cell Lineage/genetics
• Cell Self Renewal
• Chromatin/metabolism
• Enhancer of Zeste Homolog 2 Protein/metabolism
• Female
• Gene Expression Regulation
• Hematopoiesis/genetics
• Hematopoietic Stem Cells/cytology
• Homeostasis
• Male
• Mice, Inbred C57BL
• Models, Biological
• Polycomb Repressive Complex 2/genetics
• Polycomb Repressive Complex 2/metabolism

• T32 HD075735 NICHD NIH HHS
• U24 CA224260 NCI NIH HHS

• RbAp48
• aging
• hippocampus
• memory
• osteocalcin

• AK027294
• EZH1
• Glycyrrhiza glabra
• NPC
• lncRNA

Background: When neonatal rats suffer hypoxic-ischemic brain injury (HIBI), autophagy is over-activated in the hippocampus, and inhibition of autophagy provides neuroprotection. The aim of this study was to investigate the possible roles of autophagy and Ezh2-regulated Pten/Akt/mTOR pathway in sevoflurane post-conditioning (SPC)-mediated neuroprotection against HIBI in neonatal rats.

Methods: Seven-day-old Sprague–Dawley rats underwent left common artery ligation followed by 2 h hypoxia as described in the Rice–Vannucci model. The roles of autophagy and the Ezh2-regulated Pten/Akt/mTOR signaling pathway in the neuroprotection conferred by SPC were examined by left-side intracerebroventricular injection with the autophagy activator rapamycin and the Ezh2 inhibitor GSK126.

Results: SPC was neuroprotective against HIBI through the inhibition of over-activated autophagy in the hippocampus as characterized by the rapamycin-induced reversal of neuronal density, neuronal morphology, cerebral morphology, and the expression of the autophagy markers, LC3B-II and Beclin1. SPC significantly increased the expression of Ezh2, H3K27me3, pAkt, and mTOR and decreased the expression of Pten induced by HI. The Ezh2 inhibitor, GSK126, significantly reversed the SPC-induced changes in expression of H3K27me3, Pten, pAkt, mTOR, LC3B-II, and Beclin1. Ezh2 inhibition also reversed SPC-mediated attenuation of neuronal loss and behavioral improvement in the Morris water maze.

Conclusion: These results indicate that SPC inhibits excessive autophagy via the regulation of Pten/Akt/mTOR signaling by Ezh2 to confer neuroprotection against HIBI in neonatal rats.

• Ezh2
• Pten/Akt/mTOR
• autophagy
• hypoxic-ischemic brain injury
• neonatal rat
• sevoflurane post-conditioning

Polycomb repressive complex (PRC) 2 represses transcription through histone H3K27 trimethylation (H3K27me3). We previously reported that the hematopoietic-cell-specific deletion of Ezh2, encoding a PRC2 enzyme, induced myelodysplastic syndrome (MDS) in mice, whereas the concurrent Ezh1 deletion depleted hematopoietic stem and progenitor cells (HSPCs). We herein demonstrated that mice with only one Ezh1 allele (Ezh1^+/-Ezh2^Δ/Δ) maintained HSPCs. A chromatin immunopreciptation sequence analysis revealed that residual PRC2 preferentially targeted genes with high levels of H3K27me3 and H2AK119 monoubiquitination (H2AK119ub1) in HSPCs (designated as Ezh1 core target genes), which were mostly developmental regulators, and maintained H3K27me3 levels in Ezh1^+/-Ezh2^Δ/Δ HSPCs. Even upon the complete depletion of Ezh1 and Ezh2, H2AK119ub1 levels were largely retained, and only a minimal number of Ezh1 core targets were de-repressed. These results indicate that genes marked with high levels of H3K27me3 and H2AK119ub1 are the core targets of polycomb complexes in HSPCs as well as MDS stem cells.

•

One allele of Ezh1 is enough to maintain self-renewing HSCs and MDS stem cells

• Biological Sciences
• Cell Biology
• Developmental Biology
• Genetics
• Immunology
• Molecular Biology

• Antipsychotics
• Epigenetics
• Prefrontal cortex
• Schizophrenia
• miR-132, EZH1, microRNA

Neurons in the central nervous system (CNS) lose their intrinsic ability and fail to regenerate, but the underlying mechanisms are largely unknown. Polycomb group (PcG) proteins, which include PRC1 and PRC2 complexes function as gene repressors and are involved in many biological processes. Here we report that PRC1 components (polycomb chromobox (CBX) 2, 7, and 8) are novel regulators of axon growth and regeneration. Especially, knockdown of CBX7 in either embryonic cortical neurons or adult dorsal root ganglion (DRG) neurons enhances their axon growth ability. Two important transcription factors GATA4 and SOX11 are functional downstream targets of CBX7 in controlling axon regeneration. Moreover, knockdown of GATA4 or SOX11 in cultured DRG neurons inhibits axon regeneration response from CBX7 downregulation in DRG neurons. These findings suggest that targeting CBX signaling pathway may be a novel approach for promoting the intrinsic regenerative capacity of damaged CNS neurons.

• CaMKII
• H3K27Ac
• NMDAR
• brain
• cultures
• dendrites
• histone modification
• neuron
• spines

• Acetylation
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors
• Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics
• Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
• Cells, Cultured
• Cyclic AMP Response Element-Binding Protein/metabolism
• Dendrites/drug effects
• Dendrites/enzymology
• Gestational Age
• Hippocampus/drug effects
• Hippocampus/embryology
• Hippocampus/enzymology
• Histones/metabolism
• Mutation
• Neurogenesis/drug effects
• Neuronal Plasticity/drug effects
• Peptides/pharmacology
• Phenotype
• Protein Binding
• Protein Interaction Domains and Motifs
• Protein Kinase Inhibitors/pharmacology
• Protein Processing, Post-Translational
• RNA Interference
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate/genetics
• Receptors, N-Methyl-D-Aspartate/metabolism
• Signal Transduction
• Transfection

• ATF
• Alzheimer’s disease
• PSD-95
• ZFP
• epigenetics

• Alzheimer Disease/genetics
• Alzheimer Disease/pathology
• Alzheimer Disease/physiopathology
• Alzheimer Disease/psychology
• Amyloid beta-Protein Precursor/genetics
• Animals
• Behavior, Animal
• Cognition
• Disease Models, Animal
• Disks Large Homolog 4 Protein/genetics
• Epigenesis, Genetic
• Epigenetic Repression
• Hippocampus/metabolism
• Histone Code
• Humans
• Memory
• Mice
• Mice, Transgenic
• Rats
• Transcriptional Activation
• Zinc Fingers

• R01 NS093941 NINDS NIH HHS

Pb is a pervasive environmental threat to human health. Although remarkable progress has been made in its neurotoxicity, the precise molecular mechanisms underlying this widespread toxicant still remain elusive. In this study, the detailed roles of EZH2, a transcriptional repressor, in the regulation of Pb-led neurotoxicity were investigated, highlighting its sub-functionalization, compartmentalization, functional chaperones and downstream partners. Based on the findings, EZH2’s protein levels were significantly reduced in response to Pb treatment; EZH2’s gain-of-function trials recovered the dampened neurite outgrowth; EZH2’ recruitment to ploycomb complex, as well as its interaction with cytosolic Vav1, was altered in a distinct manner, suggesting that EZH2’s multiple roles were markedly redistributed in this context; EZH2’s cytosolic and nuclear presence differed in their respective response towards Pb treatment; EZH2 directly occupied the promoters of EGR2, NGFR and CaMKK2, genes responsible for various nerve functions and repair mechanisms, and essentially contributed to their aberrant expression. It indicated that EZH2 mediated the dynamic changes of a cascade of key molecules and consequently the related neurological impairments. In summary, EZH2 emerges as a central player to regulate Pb-led neurotoxicity in a transcriptionally dependent and independent manner, and thereby provided a promising molecular target for medical intervention.

• EZH2
• PRC2
• Pb
• chromatin immunoprecipitation
• neurotoxicity