RESUMEN
Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a â¼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.
Asunto(s)
Trastorno del Espectro Autista/genética , Haploinsuficiencia/genética , Histona Desacetilasas/metabolismo , Discapacidad Intelectual/genética , Proteínas Represoras/genética , Acetilación , Adolescente , Animales , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Femenino , Histonas/química , Histonas/metabolismo , Humanos , Lactante , Larva/genética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Modelos Moleculares , Mutación , Proteínas Represoras/deficiencia , Proteínas Represoras/metabolismo , Síndrome , Adulto Joven , Pez Cebra/genética , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genéticaRESUMEN
Aneuploidy has been recognized as a hallmark of tumorigenesis for more than 100 years, but the connection between chromosomal errors and malignant growth has remained obscure. New evidence emerging from both basic and clinical research has illuminated a complicated relationship: despite its frequency in human tumours, aneuploidy is not a universal driver of cancer development and instead can exert substantial tumour-suppressive effects. The specific consequences of aneuploidy are highly context dependent and are influenced by a cell's genetic and environmental milieu. In this Review, we discuss the diverse facets of cancer biology that are shaped by aneuploidy, including metastasis, drug resistance and immune recognition, and we highlight aneuploidy's distinct roles as both a tumour promoter and an anticancer vulnerability.
Asunto(s)
Aneuploidia , Resistencia a Antineoplásicos/genética , Neoplasias/genética , Escape del Tumor/inmunología , Animales , Carcinogénesis/genética , Carcinogénesis/inmunología , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Modelos Animales de Enfermedad , Síndrome de Down/complicaciones , Síndrome de Down/genética , Resistencia a Antineoplásicos/inmunología , Humanos , Ratones , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/inmunología , Neoplasias/inmunología , Fenotipo , Escape del Tumor/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Epidemiologic studies indicate an association between exposure to cadmium (Cd) and placental-related pregnancy disorders. While a precise mechanism is unknown, oxidative imbalance and dysregulation of the hypoxia inducible factor (HIF) and transforming growth factor beta (TGF-ß) pathways have been implicated in placental disease pathogenesis. Here we investigated key oxidative and placentation pathways in JEG-3 placental trophoblast cells treated with Cd alone, environmental water samples predominated by Cd with low concentrations of other metals (e.g. inorganic arsenic (iAs)) collected from a waste-site, and a matched mixture of Cd and iAs prepared in the laboratory. The induction of cytosolic reactive oxygen species (ROS), expression of metallothionein (MT) isoforms, HIF1α and downstream targets, and expression of TGFß pathway-associated genes and proteins were assessed. Additionally, the effect of pre-treatment with the antioxidant N-acetyl cysteine (NAC) on ROS generation and effects on HIF, MT and TGF-ß signaling pathways was examined. Cd and Cd-mixture treated cells displayed higher levels of ROSs with accompanying disruption of HIF and TGFß pathway signaling versus controls, with the Cd-mixture eliciting a greater effect. Conversely, pretreatment with NAC reduced Cd-induced ROS production and disruption of HIF, MT and TGFß pathway signaling. The results indicate that treatment of placental trophoblast cells with Cd results in increased production of ROSs that disrupt placentation pathways involved in disease pathogenesis. Also, co-occurrence of Cd with other toxic metals, particularly arsenic, may induce detrimental health effects that are currently underestimated when analyzed as single metals.
Asunto(s)
Cadmio/toxicidad , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Placenta/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Trofoblastos/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Placenta/citología , Placenta/efectos de los fármacos , Embarazo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Trofoblastos/efectos de los fármacosRESUMEN
Exposure to elevated levels of the toxic metals inorganic arsenic (iAs) and cadmium (Cd) represents a major global health problem. These metals often occur as mixtures in the environment, creating the potential for interactive or synergistic biological effects different from those observed in single exposure conditions. In the present study, environmental mixtures collected from two waste sites in China and comparable mixtures prepared in the laboratory were tested for toxicogenomic response in placental JEG-3 cells. These cells serve as a model for evaluating cellular responses to exposures during pregnancy. One of the mixtures was predominated by iAs and one by Cd. Six gene biomarkers were measured in order to evaluate the effects from the metal mixtures using dose and time-course experiments including: heme oxygenase 1 (HO-1) and metallothionein isoforms (MT1A, MT1F and MT1G) previously shown to be preferentially induced by exposure to either iAs or Cd, and metal transporter genes aquaporin-9 (AQP9) and ATPase, Cu(2+) transporting, beta polypeptide (ATP7B). There was a significant increase in the mRNA expression levels of ATP7B, HO-1, MT1A, MT1F, and MT1G in mixture-treated cells compared to the iAs or Cd only-treated cells. Notably, the genomic responses were observed at concentrations significantly lower than levels found at the environmental collection sites. These data demonstrate that metal mixtures increase the expression of gene biomarkers in placental JEG-3 cells in a synergistic manner. Taken together, the data suggest that toxic metals that co-occur may induce detrimental health effects that are currently underestimated when analyzed as single metals.