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Molecular biomarkers require the reproducible capture of disease-associated changes and are ideally sensitive, specific and accessible with minimal invasiveness to patients. Exosomes are a subtype of extracellular vesicles that have gained attention as potential biomarkers. They are released by all cell types and carry molecular cargo that reflects the functional state of the cells of origin. These characteristics make them an attractive means of measuring disease-related processes within the central nervous system (CNS), as they cross the blood-brain barrier (BBB) and can be captured in peripheral blood. In this review, we discuss recent progress made toward identifying blood-based protein and RNA biomarkers of several neurodegenerative diseases from circulating, CNS cell-derived exosomes. Given the lack of standardized methodology for exosome isolation and characterization, we discuss the challenges of capturing and quantifying the molecular content of exosome populations from blood for translation to clinical use.
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BACKGROUND: Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end. METHODS: To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes. RESULTS: Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical-histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets. CONCLUSIONS: Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.
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Sequenciamento do Exoma , Estudos de Associação Genética , Fenótipo , Humanos , Masculino , Feminino , Predisposição Genética para Doença , Mutação , Exoma/genética , Linhagem , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/diagnóstico , Doenças Musculares/genética , Doenças Musculares/diagnóstico , Doenças Musculares/congênito , Criança , AdultoRESUMO
BACKGROUND AND PURPOSE: Low-field 64mT portable brain MRI (pMRI) has recently shown diagnostic promise for MS. This study aimed to evaluate the utility of pMRI in assessing dissemination in space (DIS) in patients presenting with optic neuritis and determine whether deploying pMRI in the MS clinic can shorten the time from symptom onset to MRI. MATERIALS AND METHODS: Newly diagnosed optic neuritis patients referred to a tertiary academic MS center from July 2022 to January 2024 underwent both point-of-care pMRI and subsequent conventional 3T MRI (cMRI). Images were evaluated for periventricular (PV), juxtacortical (JC) and infratentorial (IT) lesions. DIS was determined on brain MRI per 2017 McDonald criteria. Test characteristics were computed using cMRI as the reference. Interrater and intermodality agreement between pMRI and cMRI were evaluated using Cohen's kappa. Time from symptom onset to pMRI and cMRI during the study period was compared to the preceding 1.5 years before pMRI implementation using Kruskal-Wallis with post-hoc Dunn's tests. RESULTS: Twenty patients (median age: 32.5 [IQR, 28-40]; 80% females) were included, of whom 9 (45%) and 5 (25%) had DIS on cMRI and pMRI, respectively. Median time interval between pMRI and cMRI was 7 days (IQR, 3.5-12.5). Interrater agreement was very good for PV (95%, κ=0.89), and good for JC and IT lesions (90%, κ=0.69 for both). Intermodality agreement was good for PV (90%, κ=0.80) and JC (85%, κ=0.63), and moderate for IT lesions (75%, κ=0.42) and DIS (80%, κ=0.58). pMRI had a sensitivity of 56% and specificity of 100% for DIS.The median time from symptom onset to pMRI was significantly shorter (8.5 days [IQR 7-12]) compared to the interval to cMRI before pMRI deployment (21 days [IQR 8-49], n=50) and after pMRI deployment (15 days [IQR 12-29], n=30) (both p<0.01). Time from symptom onset to cMRI in those periods was not significantly different (p=0.29). CONCLUSIONS: In optic neuritis patients, pMRI exhibited moderate concordance, moderate sensitivity and high specificity for DIS compared to cMRI. Its integration into the MS clinic reduced the time from symptom onset to MRI. Further studies are warranted to evaluate the role of pMRI in expediting early MS diagnosis and as an imaging tool in resource-limited settings. ABBREVIATIONS: pMRI = portable MRI; cMRI = conventional MRI; pwMS = patients with MS; PV = periventricular; JC= juxtacortical; IT = infratentorial; DIS = dissemination in space.
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Experimental autoimmune encephalomyelitis (EAE) is a common immune-based model of multiple sclerosis (MS). This disease can be induced in rodents by active immunization with protein components of the myelin sheath and Complete Freund's adjuvant (CFA) or by the transfer of myelin-specific T effector cells from rodents primed with myelin protein/CFA into naïve rodents. The severity of EAE is typically scored on a 5-point clinical scale that measures the degree of ascending paralysis, but this scale is not optimal for assessing the extent of recovery from EAE. For example, clinical scores remain high in some EAE models (e.g., myelin oligodendrocyte glycoprotein [MOG] peptide-induced model of EAE) despite the resolution of inflammation. Thus, it is important to complement clinical scoring with histological scoring of EAE, which also provides a means to study the underlying mechanisms of cellular injury in the central nervous system (CNS). Here, a simple protocol is presented to prepare and stain spinal cord and brain sections from mice and to score inflammation, demyelination, and axonal injury in the spinal cord. The method for scoring leukocyte infiltration in the spinal cord can also be applied to score brain inflammation in EAE. A protocol for measuring soluble neurofilament light (sNF-L) in the serum of mice using a Small Molecule Assay (SIMOA) assay is also described, which provides feedback on the extent of overall CNS injury in live mice.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Encefalomielite Autoimune Experimental/induzido quimicamente , Esclerose Múltipla/patologia , Medula Espinal/patologia , Inflamação/patologia , Axônios/patologia , Glicoproteína Mielina-Oligodendrócito , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/efeitos adversosRESUMO
BACKGROUND: There are no specific, evidence-based recommendations for the management of individuals with radiologically isolated syndrome. Imaging and blood biomarkers may have prognostic utility. OBJECTIVE: To determine whether plasma neurofilament light protein (NfL) or glial fibrillary acidic protein (GFAP) levels in people with radiologically isolated syndrome correlate with imaging measures that have been shown to be associated with negative clinical outcomes in people with multiple sclerosis. METHODS: Cross-sectional analysis of people with radiologically isolated syndrome. Participants underwent magnetic resonance imaging (MRI) of the brain and cervical spinal cord, and plasma was collected. Plasma NfL and GFAP levels were measured with a single-molecule array, and correlations with MRI measures were assessed, including the number of: T1-black holes, white-matter lesions demonstrating the central vein sign, paramagnetic rim lesions, cervical spinal cord lesions and infratentorial lesions. RESULTS: Plasma GFAP levels, but not NfL levels, showed correlations with the number of T1-black holes, white matter lesions demonstrating the central vein sign and paramagnetic rim lesions (all p < 0.05). CONCLUSION: We found correlations between plasma GFAP levels and imaging measures associated with poor clinical outcomes and chronic inflammation in individuals with radiologically isolated syndrome. Plasma GFAP may have prognostic utility in clinical trials and clinical practice.
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Doenças Desmielinizantes , Esclerose Múltipla , Humanos , Biomarcadores , Estudos Transversais , Doenças Desmielinizantes/diagnóstico por imagem , Proteína Glial Fibrilar Ácida , Filamentos Intermediários/patologia , Esclerose Múltipla/diagnóstico , Proteínas de NeurofilamentosRESUMO
BACKGROUND: Multidrug resistance-1 (MDR1) transporter limits the intracellular accumulation of chemotherapies (paclitaxel, anthracyclines) used in breast cancer (BC) treatment. In addition to tumor cells, MDR1 is expressed on immune cell subsets in which it confers chemoresistance. Among human T cells, MDR1 is expressed by most CD8+ T cells, and a subset of CD4+ T helper (Th) cells. Here we explored the expression, function and regulation of MDR1 on CD4+ T cells and investigated the role of this population in response to neoadjuvant chemotherapy (NAC) in BC. METHODS: Phenotypic and functional characteristics of MDR1+ CD4 Th cells were assessed on blood from healthy donors and patients with BC by flow cytometry. These features were extended to CD4+ Th cells from untreated breast tumor by flow cytometry and RNA-sequencing (RNA-seq). We performed in vitro polarization assays to decipher MDR1 regulation on CD4 Th cells. We evaluated in vitro the impact of chemotherapy agents on MDR1+ CD4+ Th cells. We analyzed the impact of NAC treatment on MDR1+ CD4+ Th cells from blood and tumors and their association with treatment efficacy in two independent BC cohorts and in a public RNA-seq data set of BC tumor biopsies before and after NAC. Finally, we performed single cell (sc) RNAseq of blood CD4+ memory T cells from NAC-treated patients and combined them with an scRNAseq public data set. RESULTS: MDR1+ CD4 Th cells were strongly enriched in Th1.17 polyfunctional cells but also in Th17 cells, both in blood and untreated breast tumor tissues. Mechanistically, Tumor growth factor (TGF)-ß1 was required for MDR1 induction during in vitro Th17 or Th1.17 polarization. MDR1 expression conferred a selective advantage to Th1.17 and Th17 cells following paclitaxel treatment in vitro and in vivo in NAC-treated patients. scRNAseq demonstrated MDR1 association with tumor Th1.17 and Th with features of cytotoxic cells. Enrichment in MDR1+ CD4+ Th1.17 and Th17 cells, in blood and tumors positively correlated with pathological response. Absence of early modulation of Th1.17 and Th17 in NAC-resistant patients, argue for its use as a biomarker for chemotherapy regimen adjustment. CONCLUSION: MDR1 favored the enrichment of Th1.17 and Th17 in blood and tumor after NAC that correlated to clinical response.
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Neoplasias da Mama , Humanos , Feminino , Linfócitos T CD8-Positivos , Terapia Neoadjuvante , Linfócitos T CD4-Positivos , Células Th17 , Paclitaxel/farmacologia , Paclitaxel/uso terapêuticoRESUMO
I-III-VI2 group quantum dots (QDs) have attracted high attention in photoelectronic conversion applications, especially for QD-sensitized solar cells (QDSSCs). This group of QDs has become the mainstream light-harvesting material in QDSSCs due to the ability to tune their electronic properties through size, shape, and composition and the ability to assemble the nanocrystals on the surface of TiO2. Moreover, these nanocrystals can be produced relatively easily via cost-effective solution-based synthetic methods and are composed of low-toxicity elements, which favors their integration into the market. This review describes the methods developed to prepare I-III-VI2 QDs (AgInS2 and CuInS2 were excluded) and control their optoelectronic properties to favor their integration into QDSSCs. Strategies developed to broaden the optoelectronic response and decrease the surface-defect states of QDs in order to promote the fast electron injection from QDs into TiO2 and achieve highly efficient QDSSCs will be described. Results show that heterostructures obtained after the sensitization of TiO2 with I-III-VI2 QDs could outperform those of other QDSSCs. The highest power-conversion efficiency (15.2%) was obtained for quinary Cu-In-Zn-Se-S QDs, along with a short-circuit density (JSC) of 26.30 mA·cm-2, an open-circuit voltage (VOC) of 802 mV and a fill factor (FF) of 71%.
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Research suggests that physical exercise can promote an anti-inflammatory and neuroprotective state. If so, increasing or optimizing exercise could be considered a 'disease-modifying intervention' in neuroinflammatory diseases, such as multiple sclerosis (MS). Exercise intervention studies conducted in animal models of MS are promising. Various aerobic and strength training regimes have been shown to delay disease onset and to reduce both the clinical and pathological disease severity in mice. However, fundamental differences between the physiology of animals and humans, the disease states studied, and the timing of exercise intervention are significant. In animal models of MS, most exercise interventions begin before disease initiation and before any clinical sign of disease. In contrast, studies in humans recruit participants on average nearly a decade after diagnosis and often once disability is established. If, as is thought to be the case for disease-modifying treatments, the immunomodulatory effect of exercise decreases with advancing disease duration, current studies may therefore fail to detect the true disease-modifying potential. Clinical studies in early disease cohorts are needed to determine the role of exercise as a disease-modifying intervention for people with MS.
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A review of the current literature shows there is no clear consensus regarding the reaction mechanisms of air-borne aromatic compounds such as toluene by photocatalytic oxidation. Potential oxidation reactions over TiO2 or TiO2-based catalysts under ultraviolet and visible (UV/VIS) illumination are most commonly considered for removal of these pollutants. Along the pathways from a model pollutant, toluene, to final mineralization products (CO2 and H2O), the formation of several intermediates via specific reactions include parallel oxidation reactions and formation of less-reactive intermediates on the TiO2 surface. The latter may occupy active adsorption sites and causes drastic catalyst deactivation in some cases. Major hazardous gas-phase intermediates are benzene and formaldehyde, classified by the International Agency for Research on Cancer (IARC) as Group 1 carcinogenic compounds. Adsorbed intermediates leading to catalyst deactivation are benzaldehyde, benzoic acid, and cresols. The three most typical pathways of toluene photocatalytic oxidation are reviewed: methyl group oxidation, aromatic ring oxidation, and aromatic ring opening.
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The widespread role of titanium (IV) oxide (TiO2) in many industries makes this substance of broad scientific interest. TiO2 can act as both a photoprotector and photocatalyst, and the potential for its role in both applications increases when present in nanometer-sized crystals. Its sunlight-scattering properties are used extensively in sunscreens. Furthermore, attempts have been made to incorporate TiO2 into dermal formulations of photolabile drugs. However, the propensity to generate reactive oxygen species (ROS) rendering this material potentially cytotoxic limits its role. Therefore, modifications of TiO2 nanoparticles (e.g., its polymorphic form, size, shape, and surface modifications) are used in an effort to reduce its photocatalytic effects. This review provides an overview of the potential risks arising from and opportunities presented by the use of TiO2 in skin care formulations.
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Dermatite Fototóxica , Nanopartículas , Humanos , Titânio/química , Óxidos , Nanopartículas/químicaRESUMO
BACKGROUND: Reports suggest a potential association between coronavirus disease 2019 (COVID-19) vaccines and acute central nervous system (CNS) inflammation. OBJECTIVE: The main objective of this study is to describe features of acute CNS inflammation following COVID-19 vaccination. METHODS: A retrospective observational cohort study was performed at the BARLO MS Centre in Toronto, Canada. Clinicians reported acute CNS inflammatory events within 60 days after a COVID-19 vaccine from March 2021 to August 2022. Clinical characteristics were evaluated. RESULTS: Thirty-eight patients (median age 39 (range: 20-82) years; 60.5% female) presented within 0-55 (median 15) days of a receiving a COVID-19 vaccine and were diagnosed with relapsing remitting multiple sclerosis (MS) (n = 16), post-vaccine transverse myelitis (n = 7), clinically isolated syndrome (n = 5), MS relapse (n = 4), tumefactive demyelination (n = 2), myelin oligodendrocyte glycoprotein antibody disease (n = 1), neuromyelitis optica spectrum disorder (n = 1), chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (n = 1) and primary autoimmune cerebellar ataxia (n = 1). Twenty-two received acute treatment and 21 started disease-modifying therapy. Sixteen received subsequent COVID-19 vaccination, of which 87.5% had no new or worsening neurological symptoms. CONCLUSION: To our knowledge, this is the largest study describing acute CNS inflammation after COVID-19 vaccination. We could not determine whether the number of inflammatory events was higher than expected.
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COVID-19 , Neuromielite Óptica , Feminino , Humanos , Masculino , Vacinas contra COVID-19/efeitos adversos , Estudos Retrospectivos , COVID-19/prevenção & controle , Recidiva Local de Neoplasia , Sistema Nervoso Central , Estudos de Coortes , Inflamação/etiologia , Vacinação/efeitos adversos , Glicoproteína Mielina-OligodendrócitoRESUMO
BACKGROUND: Elevated levels of interferons (IFNs) are a characteristic feature of systemic autoimmune rheumatic diseases (SARDs) and may be useful in predicting impending symptomatic progression in anti-nuclear antibody-positive (ANA+) individuals lacking a SARD diagnosis. Typically, these are measured by their effect on gene expression in the blood, which has limited their utility in clinical settings. Here, we assessed whether the measurement of serum IFN-α or selected IFN-induced cytokines accurately mirrors IFN-induced gene expression in ANA+ individuals and investigated their utility as biomarkers of clinical progression. METHODS: A total of 280 subjects were studied, including 50 ANA- healthy controls, 160 ANA+ individuals without a SARD diagnosis (96 asymptomatic, 64 with undifferentiated connective tissue disease), and 70 SARD patients. IFN-induced gene expression was measured by nanoString and cytokine levels by ELISA or Simoa. ANA+ individuals lacking a SARD diagnosis who had the new onset of SARD criteria over the subsequent 2 years were defined as progressors. RESULTS: Measurement of IFN-α levels by high-sensitivity ELISA or Simoa correlated much better with IFN-induced gene expression than measurement of CXCL-10 or Galectin-9 levels. Despite this, high CXCL-10 and Galectin-9 levels were better predictors of subsequent progression in ANA+ individuals than measures of IFN-α or IFN-induced gene expression with the optimal combination of predictive cytokines (CXCL-10 and IFN-α as measured by ELISA), resulting in a specificity and positive predictive value of 100%. CONCLUSION: Easily performed ELISA assays for CXCL-10 and IFN-α can be used to predict ANA+ individuals at high risk of imminent symptomatic progression.
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Doenças Autoimunes , Doenças Reumáticas , Humanos , Citocinas , Anticorpos Antinucleares , Interferon-alfa , Progressão da DoençaRESUMO
PURPOSE OF REVIEW: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic and often progressive disease course. The current disease-modifying treatments (DMTs) limit disease progression primarily by dampening immune cell activity in the peripheral blood or hindering their migration from the periphery into the CNS. New therapies are needed to target CNS immunopathology, which is a key driver of disability progression in MS. This article reviews Bruton's Tyrosine Kinase Inhibitors (BTKIs), a new class of experimental therapy that is being intensely evaluated in MS. We focus on the potential peripheral and central mechanisms of action of BTKIs and their use in recent clinical trials in MS. RECENT FINDINGS: There is evidence that some BTKIs cross the blood-brain barrier and may be superior to currently available DMTs at dampening the chronic neuroinflammatory processes compartmentalized within the CNS that contribute to progressive worsening in people withMS (pwMS). Recently, evobrutinib and tolebrutinib have shown efficacy in phase II clinical trials, and there are numerous ongoing phase III clinical trials of various BTKIs in relapsing and progressive forms of MS. Results from these clinical trials will be essential to understand the efficacy and safety of BTKIs across the spectrum of MS and keydifferences between specific BTKIs when treating pwMS. Inhibition of BTK has emerged as an attractive strategy to target cells of the adaptive and innate immune system outside and within the CNS. BTKIs carry great therapeutic potential across the MS spectrum, where key pathobiology aspects seem confined to the CNS compartment.
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Tirosina Quinase da Agamaglobulinemia , Esclerose Múltipla , Inibidores de Proteínas Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Sistema Nervoso Central , Esclerose Múltipla/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Resultado do TratamentoRESUMO
An aqueous-phase synthesis of 3-mercaptopropionic acid (3-MPA)-capped core/shell/shell ZnSeS/Cu:ZnS/ZnS QDs was developed. The influence of the Cu-dopant location on the photoluminescence (PL) emission intensity was investigated, and the results show that the introduction of the Cu dopant in the first ZnS shell leads to QDs exhibiting the highest PL quantum yield (25%). The influence of the Cu-loading in the dots on the PL emission was also studied, and a shift from blue-green to green was observed with the increase of the Cu doping from 1.25 to 7.5%. ZnSeS/Cu:ZnS/ZnS QDs exhibit an average diameter of 2.1 ± 0.3 nm and are stable for weeks in aqueous solution. Moreover, the dots were found to be photostable under the continuous illumination of an Hg-Xe lamp and in the presence of oxygen, indicating their high potential for applications such as sensing or bio-imaging.
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For several decades, nanoparticles (NPs) are becoming widely used in various industries, in electronics, agriculture, textile production or medicine [...].
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BACKGROUND: Natalizumab is a humanized monoclonal antibody used for treatment of highly active relapsing-remitting multiple sclerosis (MS). With more than 15 years of post-marketing experience with natalizumab in Canada, several real-world studies have shown the long-term efficacy and safety of natalizumab. In addition, risk stratification/mitigation strategies for progressive leukoencephalopathy (PML), an adverse effect associated with natalizumab based on the John Cunningham virus (JCV) index; treatment duration beyond 24 months; and prior exposure to immunosuppressant drugs have been developed. METHODS: A group of neurologists from various MS clinics across Canada met in September 2021 to update the 2015 Canadian practice recommendations for the use of natalizumab in persons with MS (PwMS). RESULTS: The recommendations focused on the long-term efficacy and safety data from real-world studies, patient selection according to JCV index criteria, risk management strategies for PML (including extended interval dosing), and options for switching to currently available disease-modifying therapies for MS. CONCLUSIONS: The recommendations of clinical neurologists seek to optimize the management of PwMS who may benefit from treatment with natalizumab.
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Vírus JC , Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Canadá , Humanos , Fatores Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/efeitos adversosRESUMO
In the era of the COVID-19 pandemic declared in March 2020, widespread vaccination protocols were initiated to mitigate the severity and spread of COVID-19. Although COVID-19 vaccines have been generally considered safe, adverse events post-vaccination have been reported, including the development of demyelinating disease. We report a rare case of de novo aquaporin-4-positive neuromyelitis optica spectrum disorder (NMOSD) in an 80-year-old man following BNT162b SARS-CoV-2 vaccination to raise the awareness of this possible severe adverse event in an older adult. An 80-year-old South Asian man presented 2 days following his second dose of the Pfizer-BioNTech COVID-19 mRNA BNT162b2 vaccine with progressive left-sided leg weakness and numbness resulting in falls. MRI of the spine revealed a longitudinally extensive transverse myelitis from T3-T4 to T9-T10. Serum antibody testing revealed positive aquaporin-4 (AQP4) antibodies. He was diagnosed with AQP4-positive NMOSD and was treated with high-dose intravenous methylprednisolone and plasma exchange with some improvement. He was subsequently treated with mycophenolate mofetil and a slow steroid wean. This case report adds to the existing literature and suggests that COVID-19 vaccinations may trigger de novo NMOSD or NMOSD relapses in some individuals. Although rare, our patient presented with new-onset NMOSD in his 80 s following COVID-19 vaccination. As such, it is relevant to consider AQP4 testing in those presenting with a post-vaccination myelitis, regardless of age. Ongoing vaccine surveillance and research are needed to understand the risk of NMOSD post-COVID-19 vaccinations further.
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Mammalian circadian oscillators are built on a feedback loop in which the activity of the transcription factor CLOCK-BMAL1 is repressed by the PER-CRY complex. Here, we show that murine Per-/- fibroblasts display aberrant nucleosome occupancy around transcription start sites (TSSs) and at promoter-proximal and distal CTCF sites due to impaired histone H2A.Z deposition. Knocking out H2A.Z mimicked the Per null chromatin state and disrupted cellular rhythms. We found that endogenous mPER2 complexes retained CTCF as well as the specific H2A.Z-deposition chaperone YL1-a component of the ATP-dependent remodeler SRCAP and p400-TIP60 complex. While depleting YL1 or mutating chaperone-binding sites on H2A.Z lengthened the circadian period, H2A.Z deletion abrogated BMAL1 chromatin recruitment and promoted its proteasomal degradation. We propose that a PER2-mediated H2A.Z deposition pathway (1) compacts CLOCK-BMAL1 binding sites to establish negative feedback, (2) organizes circadian chromatin landscapes using CTCF and (3) bookmarks genomic loci for BMAL1 binding to impinge on the positive arm of the subsequent cycle.