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BACKGROUND: Abnormal expression of splicing factor 3A subunit 3 (SF3A3), a component of the spliceosome, has been confirmed to be related to the occurrence and development of various cancers. However, the expression and function of SF3A3 in bladder cancer (BC) remains unclear. METHODS: The SF3A3 mRNA and protein level were measured in clinical samples and cell lines by quantitative real-time PCR, Western blot and immunofluorescence staining. Evaluate the clinical correlation between SF3A3 expression and clinicopathological characteristics through statistical analysis in BC patients. The function of SF3A3 in BC cells was determined in vitro using MTT and colony analysis. Co-immunoprecipitation (CoIP) assay was used to detected E2F6 and KDM5C interaction. Luciferase reporter and chromatin immunoprecipitation (ChIP) were used to examine the relationship between E2F6/KDM5C and SF3A3 expression. RESULTS: In the present study, we demonstrated that expression of SF3A3 was elevated in BC tissue compared to the normal bladder tissue. Importantly, the upregulation of SF3A3 in patients was correlated with poor prognosis. Additionally, overexpression of SF3A3 promoted while depletion of SF3A3 reduced the growth of BC cells in vivo and in vitro. Data from the TCGA database and clinical samples revealed that hypomethylation of the DNA promoter leads to high expression of SF3A3 in BC tissue. We found that upregulation of lysine-specific demethylase 5C (KDM5C) promotes SF3A3 expression via hypomethylation of the DNA promoter. The transcription factor E2F6 interacts with KDM5C, recruits KDM5C to the SF3A3 promoter, and demethylates the GpC island of H3K4me2, leading to high SF3A3 expression and BC progression. CONCLUSIONS: The results demonstrated that depletion of the KDM5C/SF3A3 prevents the growth of BC in vivo and in vitro. The E2F6/KDM5C/SF3A3 pathway may be a potential therapeutic target for BC treatment.
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BACKGROUND: Lysine(K)-specific demethylase 5C (KDM5C) dysfunction causes X-linked syndromic intellectual developmental disorder Claes-Jensen type in male patients. The clinical presentations of female individuals with heterozygous KDM5C variations vary widely and are only now beginning to be characterized in detail. CASE PRESENTATION: Herein, we identified a novel de novo heterozygous nonsense variation of KDM5C (c.3533C > A, p.S1178X) in a sporadic 4-year-old Chinese girl, who presented with Claes-Jensen type-like phenotypes, such as moderate developmental delay, serious expressive language delay, short stature, microcephaly, and typical facial particularities. Moreover, X-chromosome inactivation (XCI) analysis showed no significant skewed X-inactivation. CONCLUSION: The report expands the genotype of KDM5C variation in female patients, delineates the phenotype of affected females in this well-known X-linked disorder, and also reinforces the necessity to consider this X-linked gene, KDM5C, in sporadic female patients.
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Discapacidad Intelectual Ligada al Cromosoma X , Masculino , Femenino , Humanos , Mutación , Discapacidad Intelectual Ligada al Cromosoma X/genética , Fenotipo , Histona Demetilasas/genéticaRESUMEN
Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)-a negative KDM5C target-and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher KDM5C and HIF1A levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High NANOG and IL6 levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5CHigh subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Línea Celular Tumoral , Cromatina/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/metabolismo , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Hipoxia/genética , Interleucina-6/metabolismo , Lisina/metabolismo , Oxígeno/metabolismo , Survivin/genética , Factores de Transcripción/metabolismo , Microambiente Tumoral/genéticaRESUMEN
The X-linked gene encoding aristaless-related homeobox (ARX) is a bi-functional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders (NDDs); these include cortical malformations, paediatric epilepsy, intellectual disability (ID) and autism. In addition to point mutations, duplications of the ARX locus have been detected in male patients with ID. These rearrangements include telencephalon ultraconserved enhancers, whose structural alterations can interfere with the control of ARX expression in the developing brain. Here, we review the structural features of 15 gain copy-number variants (CNVs) of the ARX locus found in patients presenting wide-ranging phenotypic variations including ID, speech delay, hypotonia and psychiatric abnormalities. We also report on a further novel Xp21.3 duplication detected in a male patient with moderate ID and carrying a fully duplicated copy of the ARX locus and the ultraconserved enhancers. As consequences of this rearrangement, the patient-derived lymphoblastoid cell line shows abnormal activity of the ARX-KDM5C-SYN1 regulatory axis. Moreover, the three-dimensional (3D) structure of the Arx locus, both in mouse embryonic stem cells and cortical neurons, provides new insight for the functional consequences of ARX duplications. Finally, by comparing the clinical features of the 16 CNVs affecting the ARX locus, we conclude that-depending on the involvement of tissue-specific enhancers-the ARX duplications are ID-associated risk CNVs with variable expressivity and penetrance.
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Genes Homeobox , Discapacidad Intelectual , Animales , Niño , Proteínas de Homeodominio/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Ratones , Mutación , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Stroke is a sexually dimorphic disease. Previous studies have found that young females are protected against ischemia compared to males, partially due to the protective effect of ovarian hormones, particularly estrogen (E2). However, there are also genetic and epigenetic effects of X chromosome dosage that contribute to stroke sensitivity and neuroinflammation after injury, especially in the aged. Genes that escape from X chromosome inactivation (XCI) contribute to sex-specific phenotypes in many disorders. Kdm5c and kdm6a are X escapee genes that demethylate H3K4me3 and H3K27me3, respectively. We hypothesized that the two demethylases play critical roles in mediating the stroke sensitivity. METHODS: To identify the X escapee genes involved in stroke, we performed RNA-seq in flow-sorted microglia from aged male and female wild type (WT) mice subjected to middle cerebral artery occlusion (MCAO). The expression of these genes (kdm5c/kdm6a) were confirmed in four core genotypes (FCG) mice and in post-mortem human stroke brains by immunohistochemistry (IHC), Western blot, and RT-PCR. Chromatin immunoprecipitation (ChIP) assays were conducted to detect DNA levels of inflammatory interferon regulatory factor (IRF) 4/5 precipitated by histone H3K4 and H3K27 antibodies. Manipulation of kdm5c/kdm6a expression with siRNA or lentivirus was performed in microglial culture, to determine downstream pathways and examine the regulatory roles in inflammatory cytokine production. RESULTS: Kdm5c and kdm6a mRNA levels were significantly higher in aged WT female vs. male microglia, and the sex difference also existed in ischemic brains from FCG mice and human stroke patients. The ChIP assay showed the IRF 4/5 had higher binding levels to demethylated H3K4 or H3K27, respectively, in female vs. male ischemic microglia. Knockdown or over expression of kdm5c/kdm6a with siRNA or lentivirus altered the methylation of H3K4 or H3K27 at the IRF4/5 genes, which in turn, impacted the production of inflammatory cytokines. CONCLUSIONS: The KDM-Histone-IRF pathways are suggested to mediate sex differences in cerebral ischemia. Epigenetic modification of stroke-related genes constitutes an important mechanism underlying the ischemic sexual dimorphism.
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Epigénesis Genética/genética , Inflamación/genética , Accidente Cerebrovascular Isquémico/genética , Caracteres Sexuales , Cromosoma X/genética , Anciano , Anciano de 80 o más Años , Animales , Inmunoprecipitación de Cromatina , Citocinas/biosíntesis , Femenino , Genotipo , Histona Demetilasas/genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , ARN Interferente Pequeño/genética , Transducción de Señal/genéticaRESUMEN
Loss of function variants in the lysine demethylase 5C (KDM5C) gene account for approximately 0.7-2.8% of X-linked intellectual disability (ID) cases and pose significant burdens for patients and their caregivers. To date, 45 unique variants in KDM5C have been reported in individuals with ID. As a rare disorder, its etiology and natural history remain an area of active investigation, with treatment limited to symptom management. Previous studies have found that males present with moderate to severe ID with significant syndromic comorbidities such as epilepsy, short stature, and craniofacial abnormalities. Although not as well characterized, females have been reported to predominantly display mild to moderate ID with approximately half being asymptomatic. Here, we present caregiver-reported data for 37 unrelated individuals with pathogenic variants in KDM5C; the largest cohort reported to-date. We find that up to 70% of affected females were reported to display syndromic features including gastrointestinal dysfunction and hearing impairment. Additionally, more than half of individuals reported a diagnosis of autism spectrum disorder or described features consistent with this spectrum. Our data thus provide further evidence of sexually dimorphic heterogeneity in disease presentation and suggest that pathogenic variants in KDM5C may be more common than previously assumed.
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Enfermedades Genéticas Ligadas al Cromosoma X/genética , Histona Demetilasas/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Adolescente , Adulto , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/genética , Cuidadores , Niño , Preescolar , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/epidemiología , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/epidemiología , Mutación/genética , Adulto JovenRESUMEN
BACKGROUND: Pathogenic variants in KDM5C are a cause of X-linked intellectual disability in males. Other features in males include short stature, dysmorphic features, seizures and spasticity. In some instances, female relatives were noted to have learning difficulties and mild intellectual disabilities, but full phenotypic descriptions were often incomplete. Recently, detailed phenotypic features of five affected females with de novo variants were described. (Clin Genet 98:43-55, 2020) Four individuals had a protein truncating variant and 1 individual had a missense variant. All five individuals had developmental delay/intellectual disability and three neurological features. CASE PRESENTATION: Here we report a three-year-old female with global developmental delay, hypotonia and ataxia. Through whole exome sequencing, a de novo c.1516A > G (p.Met506Val) variant in KDM5C was identified. This missense variant is in the jumonji-C domain of this multi domain protein where other missense variants have been previously reported in KDM5C related disorder. The KDM5C gene is highly intolerant to functional variation which suggests its pathogenicity. The probands motor delays and language impairment is consistent with other reported female patients with de novo variants in KDM5C. However, other features reported in females (distinctive facial features, skeletal abnormalities, short stature and endocrine features) were absent. To the best of our knowledge, our proband is the first female patient reported with a diagnosis of ataxia. CONCLUSIONS: This case report provides evidence for an emerging and phenotypic variability that adds to the literature of the role of KDM5C in females with neurodevelopmental disorders as well as movement disorders.
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Discapacidades del Desarrollo , Discapacidad Intelectual , Ataxia , Niño , Preescolar , Discapacidades del Desarrollo/genética , Femenino , Histona Demetilasas , Humanos , Discapacidad Intelectual/genética , Masculino , Hipotonía Muscular , Fenotipo , Secuenciación del ExomaRESUMEN
BACKGROUND: The sequencing of the renal cell carcinoma (RCC) genome has detected several mutations with prognostic meaning. The association between visceral adipose tissue (VAT) and clear cell renal cell carcinoma (ccRCC) is well known. The relationship among abdominal adipose tissue distribution and ccRCC-VHL and KDM5C genetic mutations is, to the knowledge of the authors, not known. METHODS: In this retrospective study, we enrolled 97 Caucasian male patients divided into three groups: the control group (n = 35), the ccRCC-VHL group (n = 52) composed of ccRCC patients with VHL mutations and ccRCC-KDM5C group (n = 10) composed of ccRCC patients with KDM5C mutation. Total adipose tissue (TAT) area, VAT area and subcutaneous adipose tissue (SAT) area were measured in the groups. VAT/SAT ratio was calculated for each subject. RESULTS: Statistically significant differences between ccRCC-KDM5C group and ccRCC-VHL group were obtained for TAT area (p < 0.05), VAT area (p < 0.05) and VAT/SAT ratio (p < 0.05); between ccRCC-VHL group and control group for TAT area (p < 0.001) and VAT area (p < 0.01); and between ccRCC-KDM5C group and control group for TAT area (p < 0.0001), VAT area (p < 0.0001) and SAT area (p < 0.01). CONCLUSIONS: This study demonstrates for the first time an increased amount of TAT, especially VAT, in the ccRCC-VHL and ccRCC-KDM5C groups. The effect was greater for the ccRCC-KDM5C group.
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Carcinoma de Células Renales/genética , Histona Demetilasas/genética , Grasa Intraabdominal , Neoplasias Renales/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/diagnóstico por imagen , Humanos , Neoplasias Renales/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
Emerging evidence suggests that long non-coding RNA (lncRNA) plays an important role in disease development, particularly in cancers. Recent studies with genome-wide sequencing on cervical squamous cell carcinoma and matched adjacent non-tumour tissues showed that a newly identified lncRNA-lnc_000231 was highly expressed in cervical cancers. However, the underlying mechanism through which it is activated and its role in cervical cancer progression is still unclear. In this study, first, we confirmed that lnc_000231 is up-regulated in cervical cancer cells and tumour tissues. Mechanically, we demonstrated that E6 up-regulates lnc_000231 expression through promoting its promoter region H3K4me3 modification by destabilizing KDM5C. In vitro and in vivo results showed that lnc_000231 promotes cervical cancer cell proliferation and tumour formation by acting as miR-497-5p sponge and maintaining cyclin E1 (CCNE1) expression. Thus, our studies identified a new signalling pathway through which E6 promotes cervical cancer progression. E6 hijacked KDM5C/lnc_000231/miR-497-5p/CCNE1 signalling pathway is a promising target for cervical cancer treatment in the future.
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Ciclina E/metabolismo , Progresión de la Enfermedad , Histona Demetilasas/metabolismo , MicroARNs/metabolismo , Proteínas Oncogénicas Virales/metabolismo , Proteínas Oncogénicas/metabolismo , ARN Largo no Codificante/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Acetilación , Animales , Secuencia de Bases , Carcinogénesis/genética , Carcinogénesis/patología , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metilación , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Regiones Promotoras Genéticas/genética , Estabilidad Proteica , ARN Largo no Codificante/genética , Ensayo de Tumor de Célula Madre , Regulación hacia Arriba/genéticaRESUMEN
X-linked intellectual disability (XLID) is a genetically heterogeneous condition involving more than 100 genes. To date, 35 pathogenic variants have been reported in the lysine specific demethylase 5C (KDM5C) gene. KDM5C variants are one of the major causes of moderate to severe XLID. Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity. For most of these variants, related female carriers have been reported, but phenotypic descriptions were poor. Here, we present clinical and molecular features of 19 females carrying 10 novel heterozygous variants affecting KDM5C function, including five probands with de novo variants. Four heterozygous females were asymptomatic. All affected individuals presented with learning disabilities or ID (mostly moderate), and four also had a language impairment mainly affecting expression. Behavioral disturbances were frequent, and endocrine disorders were more frequent in females. In conclusion, our findings provide evidence of the role of KDM5C in ID in females highlighting the increasing implication of XLID genes in females, even in sporadic affected individuals. Disease expression of XLID in females should be taken into consideration for genetic counseling.
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Epilepsia/genética , Genes Ligados a X/genética , Variación Genética/genética , Histona Demetilasas/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Adulto , Preescolar , Femenino , Heterocigoto , Humanos , Masculino , Fenotipo , Adulto JovenRESUMEN
With the continued increase in global human population, diverse contraception approaches have become increasingly essential, including non-hormonal male contraception. Non-hormonal approaches to contraception are very convenient; however, such options are limited because data regarding the identification and characterization of tissue/cell-specific targets and appropriate small molecule candidate contraceptives are lacking. Based on in-silico studies of genomics, transcriptomics, and proteomics, performed by mining datasets in PubMed, we first reviewed testis-, epididymis-, and germline cell-specific genes/proteins, with the aim of presenting evidence that many of these could become 'druggable' targets for the development of non-hormonal male contraceptives in the future. Although many hurdles remain before the successful therapeutic use of non-hormonal contraceptive, to facilitate this approach, we describe here the changing perspectives on several potential non-hormonal contraceptives (e.g. small molecules, plant extracts, etc.) that are under development; continued effort may yield marketable products. Further, we highlight specific enzymes within the histone lysine demethylase subfamily that play a central role in germ line regulation. In particular, we focused on several prospective candidate small-molecules suggested to interact with the catalytic domain of histone lysine demethylase KDM5B, which is ubiquitously expressed in the testis/spermatozoa of both mice and human.
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Anticoncepción , Histona Demetilasas/fisiología , Animales , Investigación Biomédica , Anticonceptivos Masculinos , Epigénesis Genética , Genómica , Humanos , Terapia Molecular Dirigida , EspermatogénesisRESUMEN
Arginine methylation of histones is one mechanism of epigenetic regulation in eukaryotic cells. Methylarginines can also be found in non-histone proteins involved in various different processes in a cell. An enzyme family of nine protein arginine methyltransferases catalyses the addition of methyl groups on arginines of histone and non-histone proteins, resulting in either mono- or dimethylated-arginine residues. The reversibility of histone modifications is an essential feature of epigenetic regulation to respond to changes in environmental factors, signalling events, or metabolic alterations. Prominent histone modifications like lysine acetylation and lysine methylation are reversible. Enzyme family pairs have been identified, with each pair of lysine acetyltransferases/deacetylases and lysine methyltransferases/demethylases operating complementarily to generate or erase lysine modifications. Several analyses also indicate a reversible nature of arginine methylation, but the enzymes facilitating direct removal of methyl moieties from arginine residues in proteins have been discussed controversially. Differing reports have been seen for initially characterized putative candidates, like peptidyl arginine deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most recent cellular, biochemical, and mass spectrometry work on arginine methylation and its reversible nature with a special focus on putative arginine demethylases, including the enzyme superfamily of Fe(II) and 2-oxoglutarate-dependent oxygenases.
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Arginina/metabolismo , Histonas/metabolismo , Animales , Arginina/análogos & derivados , Arginina/análisis , Histona Demetilasas/metabolismo , Humanos , Hidrolasas/metabolismo , Metilación , Arginina Deiminasa Proteína-Tipo 4 , Desiminasas de la Arginina Proteica , Proteína-Arginina N-Metiltransferasas/metabolismoRESUMEN
The KDM5C gene (also known as JARID1C and SMCX) is located on the X chromosome and encodes a ubiquitously expressed 1560-aa protein, which plays an important role in lysine methylation (specifically reverses tri- and di-methylation of Lys4 of histone H3). Currently, 13 missense mutations in KDM5C have been linked to X-linked mental retardation. However, the molecular mechanism of disease is currently unknown due to the experimental difficulties in expressing such large protein and the lack of experimental 3D structure. In this work, we utilize homology modeling, docking, and experimental data to predict 3D structures of KDM5C domains and their mutual arrangement. The resulting quaternary structure includes KDM5C JmjN, ARID, PHD1, JmjC, ZF domains, substrate histone peptide, enzymatic cofactors, and DNA. The predicted quaternary structure was investigated with molecular dynamic simulation for its stability, and further analysis was carried out to identify features measured experimentally. The predicted structure of KDM5C was used to investigate the effects of disease-causing mutations and it was shown that the mutations alter domain stability and inter-domain interactions. The structural model reported in this work could prompt experimental investigations of KDM5C domain-domain interaction and exploration of undiscovered functionalities. Proteins 2016; 84:1797-1809. © 2016 Wiley Periodicals, Inc.
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Coenzimas/química , ADN/química , Histona Demetilasas/química , Histonas/química , Hierro/química , Ácidos Cetoglutáricos/química , Secuencias de Aminoácidos , Sitios de Unión , Cationes Bivalentes , Coenzimas/metabolismo , Expresión Génica , Humanos , Cinética , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Mutación , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Estructura Secundaria de Proteína , Electricidad Estática , Homología Estructural de Proteína , TermodinámicaRESUMEN
Genetic reversion is the phenomenon of spontaneous gene correction by which gene function is partially or completely rescued. However, it is unknown whether this mechanism always correctly repairs mutations, or is prone to error. We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole-exome sequencing. Two affected boys have c.633delG and the other has c.631delC. We also confirmed de novo germline (c.631delC) and low-prevalence somatic (c.633delG) mutations in their mother. The two mutations are present on the same maternal haplotype, suggesting that a postzygotic somatic mutation or a reversion error occurred at an early embryonic stage in the mother, leading to switched KDM5C mutations in the affected siblings. This event is extremely unlikely to arise spontaneously (with an estimated probability of 0.39-7.5 × 10(-28) ), thus a possible reversion error is proposed here to explain this event. This study provides evidence for reversion error as a novel mechanism for the generation of somatic mutations in human diseases.
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Histona Demetilasas/genética , Discapacidad Intelectual/genética , Herencia Materna/genética , Mutación/genética , Preescolar , Exoma , Femenino , Genes Ligados a X , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Discapacidad Intelectual/fisiopatología , Masculino , Mosaicismo , Madres , Linaje , FenotipoRESUMEN
Body fat accumulation differs between males and females and is influenced by both gonadal sex (ovaries vs testes) and chromosomal sex (XX vs XY). We previously showed that an X chromosome gene, Kdm5c, is expressed at higher levels in females compared to males and correlates with adiposity in mice and humans. Kdm5c encodes a KDM5 histone demethylase that regulates gene expression by modulating histone methylation at gene promoters and enhancers. Here, we use chemical inhibition and genetic knockdown to identify a role for KDM5 activity during early stages of white and brown preadipocyte differentiation, with specific effects on white adipocyte clonal expansion, and white and brown adipocyte gene expression and mitochondrial activity. In white adipogenesis, KDM5 activity modulates H3K4 histone methylation at the Dlk1 gene promoter to repress gene expression and promote progression from preadipocytes to mature adipocytes. In brown adipogenesis, KDM5 activity modulates H3K4 methylation and gene expression of Ucp1, which is required for thermogenesis. Unbiased transcriptome analysis revealed that KDM5 activity regulates genes associated with cell cycle regulation and mitochondrial function, and this was confirmed by functional analyses of cell proliferation and cellular bioenergetics. Using genetic knockdown, we demonstrate that KDM5C is the likely KDM5 family member that is responsible for regulation of white and brown preadipocyte programming. Given that KDM5C levels are higher in females compared to males, our findings suggest that sex differences in white and brown preadipocyte gene regulation may contribute to sex differences in adipose tissue function.
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There is no safe level of air pollution for human health. Traffic-related particulate matter (PM2.5) is a major in-utero toxin, mechanisms of action of which are not fully understood. BALB/c dams were exposed to an Australian level of traffic PM2.5 (5 µg/mouse/day, intranasal, 6 weeks before mating, during gestation and lactation). Male offspring had reduced memory in adulthood, whereas memory was normal in female littermates, similar to human responses. Maternal PM2.5 exposure resulted in oxidative stress and abnormal mitochondria in male, but not female, brains. RNA-sequencing analysis showed unique sex-related changes in newborn brains. Two X-chromosome-linked histone lysine demethylases, Kdm6a and Kdm5c, demonstrated higher expression in female compared to male littermates, in addition to upregulated genes with known functions to support mitochondrial function, synapse growth and maturation, cognitive function, and neuroprotection. No significant changes in Kdm6a and Kdm5c were found in male littermates, nor other genes, albeit significantly impaired memory function after birth. In primary foetal cortical neurons, PM2.5 exposure suppressed neuron and synaptic numbers and induced oxidative stress, which was prevented by upregulation of Kdm6a or Kdm5c. Therefore, timely epigenetic adaptation by histone demethylation to open DNA for translation before birth may be the key to protecting females against prenatal PM2.5 exposure-induced neurological disorders, which fail to occur in males associated with their poor cognitive outcomes.
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Functional and phenotypic heterogeneity of dendritic cells (DCs) play crucial roles in facilitating the development of diverse immune responses essential for host protection. Here, we report that KDM5C, a histone lysine demethylase, regulates conventional or classical DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs have increased proportions of cDC2Bs and cDC1s, which is partly dependent on type I interferon (IFN) and pDCs. Loss of KDM5C results in an increase in Ly6C- pDCs, which, compared to Ly6C+ pDCs, have limited ability to produce type I IFN and more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and decreased function. In response to Listeria infection, KDM5C-deficient mice mount reduced CD8 T cell responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and critical driver of the functional properties of DCs.
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Linfocitos T CD8-positivos , Células Dendríticas , Histona Demetilasas , Células Dendríticas/metabolismo , Células Dendríticas/inmunología , Animales , Ratones , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones Endogámicos C57BL , Transcripción Genética , Interferón Tipo I/metabolismo , Presentación de AntígenoRESUMEN
T cell-driven autoimmune responses are subject to striking sex-dependent effects. While the contributions of sex hormones are well-understood, those of sex chromosomes are meeting with increased appreciation. Here, we outline what is known about the contribution of sex chromosome-linked factors to experimental autoimmune encephalomyelitis (EAE), a mouse model that recapitulates many of the T cell-driven mechanisms of multiple sclerosis (MS) pathology. Particular attention is paid to the KDM family of histone demethylases, several of which - KDM5C, KDM5D and KDM6A - are sex chromosome encoded. Finally, we provide evidence that functional inhibition of KDM5 molecules can suppress interferon (IFN)γ production from murine male effector T cells, and that an increased ratio of inflammatory Kdm6a to immunomodulatory Kdm5c transcript is observed in T helper 17 (Th17) cells from women with the autoimmune disorder ankylosing spondylitis (AS). Histone lysine demethlyases thus represent intriguing targets for the treatment of T cell-driven autoimmune disorders.
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Autoinmunidad , Encefalomielitis Autoinmune Experimental , Animales , Femenino , Humanos , Masculino , Ratones , Sistema Nervioso Central , Histona Demetilasas , Antígenos de Histocompatibilidad Menor , Linfocitos TRESUMEN
The need to take sex into account in biomedical research is now recognized and mandated by funding institutions. In laboratory rodents, such as mice, sexing is usually performed anatomically or by genotyping using multiplex or simplex PCR techniques on genomic DNA. Here we present a simple RT-PCR-based method targeting Kdm5c and Kdm5d to determine genetic sex in mouse cDNA samples, allowing for retrospective sex determination.
Asunto(s)
ADN , Animales , Ratones , ADN Complementario/genética , Estudios Retrospectivos , ADN/genética , Reacción en Cadena de la Polimerasa/métodosRESUMEN
Background: Renal cell carcinoma (RCC) is the most common renal malignancy, and may metastasize to different sites in the body via hematogenous and lymphomatous routes. The pancreas is a rare metastatic site of metastatic RCC (mRCC) and isolated pancreatic metastasis of RCC (isPMRCC) is even rarer. Results: The present report describes a case of isPMRCC that recurred 16 years after surgery. The patient responded well to the treatment with pancreaticoduodenectomy and systemic therapy, and no recurrence was recorded after 2 years. Conclusions: isPMRCC is a distinct subgroup of RCC with unique clinical characteristics that may be explained by its underlying molecular mechanisms. Surgery and systemic therapy confer survival benefits to patients with isPMRCCs, although the recurrence problem has to be paid attention to.