RESUMEN

Bosma arhinia microphthalmia syndrome (BAMS, OMIM #603457) is a rare autosomal dominant disorder caused by heterozygous variation in the SMCHD1 gene on chromosome 18p11. Clinically, it is characterized by microphthalmia, absence or hypoplasia of nose, choanal atresia, anosmia, palatal abnormalities, hypogonadotropic hypogonadism, and cryptorchidism. Here we report a Brazilian patient with a likely pathogenic variation in SMCHD1 gene (c.1418A>T; p.Glu473Val) presenting hemiarhinia associated with short stature and hypogonadotropic hypogonadism. Due to the clinical variability of BAMS, we considered that hemiarhinia, without microphthalmia, in the present case, can be considered a mild form of BAMS and could be considered for screening of SMCHD1 gene variation.

Asunto(s)

Atresia de las Coanas , Proteínas Cromosómicas no Histona , Microftalmía , Mutación Missense , Fenotipo , Niño , Humanos , Masculino , Atresia de las Coanas/genética , Atresia de las Coanas/patología , Proteínas Cromosómicas no Histona/genética , Microftalmía/genética , Microftalmía/patología , Mutación Missense/genética , Femenino , Recién Nacido , Adolescente , Adulto

RESUMEN

HJURP is overexpressed in several cancer types and strongly correlates with patient survival. However, the mechanistic basis underlying the association of HJURP with cancer aggressiveness is not well understood. HJURP promotes the loading of the histone H3 variant, CENP-A, at the centromeric chromatin, epigenetically defining the centromeres and supporting proper chromosome segregation. In addition, HJURP is associated with DNA repair but its function in this process is still scarcely explored. Here, we demonstrate that HJURP is recruited to DSBs through a mechanism requiring chromatin PARylation and promotes epigenetic alterations that favor the execution of DNA repair. Incorporation of HJURP at DSBs promotes turnover of H3K9me3 and HP1, facilitating DNA damage signaling and DSB repair. Moreover, HJURP overexpression in glioma cell lines also affected global structure of heterochromatin independently of DNA damage induction, promoting genome-wide reorganization and assisting DNA damage response. HJURP overexpression therefore extensively alters DNA damage signaling and DSB repair, and also increases radioresistance of glioma cells. Importantly, HJURP expression levels in tumors are also associated with poor response of patients to radiation. Thus, our results enlarge the understanding of HJURP involvement in DNA repair and highlight it as a promising target for the development of adjuvant therapies that sensitize tumor cells to irradiation.

Asunto(s)

Cromatina , Glioma , Humanos , Centrómero/metabolismo , Proteína A Centromérica/genética , Proteína A Centromérica/metabolismo , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Glioma/genética

RESUMEN

OBJECTIVES: Nasopharyngeal Carcinoma (NPC) is a common malignant tumor of nasopharyngeal mucosal epithelium in clinical practice. Radiotherapy and chemotherapy are the main treatment methods at present, but the therapeutic effect is still unsatisfactory. Studies have shown that exosomes and microRNAs (miRNAs) play an important role in the development of cancer. Therefore, this study aimed to investigate the effects of NPC derived exosomes on NPC and their molecular mechanisms. METHODS: Serum was collected from healthy subjects, Epstein-Barr Virus (EBV) infected patients and NPC patients (n = 9 group) and exosomes were extracted separately. High-throughput sequencing of exosomes was performed to screen differentially expressed miRNAs. The function of the screened miRNA was identified by treating NPC cells with exosomes. The target gene of miRNA was identified using the dual-luciferase assay. Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) was used to determine the levels of miR-99a-5p and Bromodomain Adjacent Tozinc finger domain protein 2A (BAZ2A). Cell Counting Kit-8 assay, flow cytometry, and wound healing assay were utilized to detect cell viability, cell cycle and apoptosis, and migration ability. The protein levels were evaluated by Western blot. RESULTS: MiR-99a-5p was identified as the most significant differentially expressed miRNA in exosomes (p < 0.05). The proliferation and migration of NPC cells were extremely facilitated by exosomes, accompanied by the suppressed apoptosis, upregulated BAZ2A, Monocyte Chemotactic Protein-1 (MCP1), and Vascular Endothelial Growth Factor A (VEGFA), and downregulation of Interleukin (IL)-1ß and Nuclear Transcription Factor-κB (NF-κB) (p < 0.05). BAZ2A was a target gene of miR-99a-5p. Furthermore, the regulatory effect of exosomes on the proliferation, migration, and apoptosis was significantly abolished by overexpression of miR-99a-5p or downregulation of BAZ2A (p < 0.05). CONCLUSION: NPC derived exosomes facilitated the proliferation and migration of NPC through regulating the miR-99a-5p/BAZ2A axis.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Exosomas , MicroARNs , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Exosomas/genética , Exosomas/metabolismo , Exosomas/patología , Infecciones por Virus de Epstein-Barr/genética , Línea Celular Tumoral , Proliferación Celular , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Regulación Neoplásica de la Expresión Génica , Proteínas que Contienen Bromodominio , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo

RESUMEN

PURPOSE: This study aimed to establish variants in CBX1, encoding heterochromatin protein 1ß (HP1ß), as a cause of a novel syndromic neurodevelopmental disorder. METHODS: Patients with CBX1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. To investigate the pathogenicity of identified variants, we performed in vitro cellular assays and neurobehavioral and cytological analyses of neuronal cells obtained from newly generated Cbx1 mutant mouse lines. RESULTS: In 3 unrelated individuals with developmental delay, hypotonia, and autistic features, we identified heterozygous de novo variants in CBX1. The identified variants were in the chromodomain, the functional domain of HP1ß, which mediates interactions with chromatin. Cbx1 chromodomain mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Cytological and chromatin immunoprecipitation experiments confirmed the reduction of mutant HP1ß binding to heterochromatin, whereas HP1ß interactome analysis demonstrated that the majority of HP1ß-interacting proteins remained unchanged between the wild-type and mutant HP1ß. CONCLUSION: These collective findings confirm the role of CBX1 in developmental disabilities through the disruption of HP1ß chromatin binding during neurocognitive development. Because HP1ß forms homodimers and heterodimers, mutant HP1ß likely sequesters wild-type HP1ß and other HP1 proteins, exerting dominant-negative effects.

Asunto(s)

Homólogo de la Proteína Chromobox 5 , Heterocromatina , Animales , Ratones , Cromatina/genética , Proteínas Cromosómicas no Histona/genética , Histonas/genética , Histonas/metabolismo

RESUMEN

Inflorescence movements in response to natural gradients of sunlight are frequently observed in the plant kingdom and are suggested to contribute to reproductive success. Although the physiological and molecular bases of light-mediated tropisms in vegetative organs have been thoroughly investigated, the mechanisms that control inflorescence orientation in response to light gradients under natural conditions are not well understood. In this work, we have used a combination of laboratory and field experiments to investigate light-mediated re-orientation of Arabidopsis thaliana inflorescences. We show that inflorescence phototropism is promoted by photons in the UV and blue spectral range (≤500 nm) and depends on multiple photoreceptor families. Experiments under controlled conditions show that UVR8 is the main photoreceptor mediating the phototropic response to narrowband UV-B radiation, and phototropins and cryptochromes control the response to narrowband blue light. Interestingly, whereas phototropins mediate bending in response to low irradiances of blue, cryptochromes are the principal photoreceptors acting at high irradiances. Moreover, phototropins negatively regulate the action of cryptochromes at high irradiances of blue light. Experiments under natural field conditions demonstrate that cryptochromes are the principal photoreceptors acting in the promotion of the heliotropic response of inflorescences under full sunlight.

Asunto(s)

Proteínas de Arabidopsis/genética , Arabidopsis/fisiología , Proteínas Cromosómicas no Histona/genética , Citocromos/genética , Fotorreceptores de Plantas/genética , Fototropismo/genética , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Citocromos/metabolismo , Fotorreceptores de Plantas/metabolismo

RESUMEN

BACKGROUND: Plant homeodomain finger protein 20-like 1 (PHF20L1) is a protein reader involved in epigenetic regulation that binds monomethyl-lysine. An oncogenic function has been attributed to PHF20L1 but its role in breast cancer (BC) is not clear. OBJECTIVES: To explore PHF20L1 promoter methylation and comprehensive bioinformatics analysis to improve understanding of the role of PHF20L1 in BC. MATERIAL AND METHODS: Seventy-four BC samples and 16 control samples were converted using sodium bisulfite treatment and analyzed with methylation-specific polymerase chain reaction (PCR). Bioinformatic analysis was performed in the BC dataset using The Cancer Genome Atlas (TCGA) trough data visualized and interpreted in the MEXPRESS website. Methylation, gene expression and survival evaluation were performed with R v. 4.0.2 software. Using multiple bioinformatic tools, we conducted a search for genes co-expressed with PHF20L1, analyzed its ontology and predicted associated miRNAs and miRNA-PHF20L1 networks. The expression and prognostic value of PHF20L1 and co-expressed genes were analyzed. RESULTS: We found demethylation in PHF20L1 promoter in both BC samples and healthy tissues. Data mining with 241 patients demonstrated changes in methylation of promoter regions in basal-like and luminal A subtypes. Expression of the PHF20L1 gene had a negative correlation with methylation. Twelve genes were co-expressed. PHF20L1 is a target of miR96-5p, miR9-5p and miR182-5p, which are involved in proliferation and metastasis. PHF20L1 gene expression was not associated with overall survival (OS), or relapse-free survival (RFS), but was associated with distant metastasis-free survival (DMFS). CONCLUSIONS: Our findings showed differences in methylation of PHF20L1 promoter region near TSS and upstream in BC subtypes; its overexpression impacted DMFS. We found that PHF20L1 is targeted by miR96-5p, miR9-5p and miR182-5p, which are involved in proliferation and metastasis, and regulates genes engaged in processes such as alternative splicing.

Asunto(s)

Neoplasias de la Mama , MicroARNs , Neoplasias de la Mama/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Metilación , MicroARNs/genética , MicroARNs/metabolismo , Recurrencia Local de Neoplasia , Regiones Promotoras Genéticas

RESUMEN

Understanding the packaging of DNA into chromatin has become a crucial aspect in the study of gene regulatory mechanisms. Heterochromatin establishment and maintenance dynamics have emerged as some of the main features involved in genome stability, cellular development, and diseases. The most extensively studied heterochromatin protein is HP1a. This protein has two main domains, namely the chromoshadow and the chromodomain, separated by a hinge region. Over the years, several works have taken on the task of identifying HP1a partners using different strategies. In this review, we focus on describing these interactions and the possible complexes and subcomplexes associated with this critical protein. Characterization of these complexes will help us to clearly understand the implications of the interactions of HP1a in heterochromatin maintenance, heterochromatin dynamics, and heterochromatin's direct relationship to gene regulation and chromatin organization.

Asunto(s)

Proteínas Cromosómicas no Histona/metabolismo , Eucromatina/metabolismo , Heterocromatina/metabolismo , Animales , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/genética , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulación de la Expresión Génica , Inestabilidad Genómica , Humanos , Elementos Aisladores , Filogenia , Unión Proteica , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas

RESUMEN

Fibrillarin is a highly conserved nucleolar methyltransferase responsible for ribosomal RNA methylation across evolution from Archaea to humans. It has been reported that fibrillarin is involved in the methylation of histone H2A in nucleoli and other processes, including viral progression, cellular stress, nuclear shape, and cell cycle progression. We show that fibrillarin has an additional activity as a ribonuclease. The activity is affected by phosphoinositides and phosphatidic acid and insensitive to ribonuclease inhibitors. Furthermore, the presence of phosphatidic acid releases the fibrillarin-U3 snoRNA complex. We show that the ribonuclease activity localizes to the GAR (glycine/arginine-rich) domain conserved in a small group of RNA interacting proteins. The introduction of the GAR domain occurred in evolution in the transition from archaea to eukaryotic cells. The interaction of this domain with phospholipids may allow a phase separation of this protein in nucleoli.

Asunto(s)

Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/metabolismo , Fosfolípidos/metabolismo , Ribonucleasas/química , Ribonucleasas/metabolismo , Proteínas Cromosómicas no Histona/genética , Células HeLa , Humanos , Mutación/genética , Dominios Proteicos , ARN Nucleolar Pequeño/metabolismo , Proteínas Recombinantes/metabolismo , Ribonucleasas/genética , Ribonucleoproteínas/metabolismo , Relación Estructura-Actividad

RESUMEN

(1) Aim: In the present paper we analyzed the transcriptome of CSCs (Cancer Stem Cells), in order to find defining molecular processes of breast cancer. (2) Methods: We performed RNA-Seq from CSCs isolated from the basal cell line MDA-MB-468. Enriched processes and networks were studied using the IPA (Ingenuity Pathway Analysis) tool. Validation was performed with qRT-PCR and the analysis of relevant genes was evaluated by overexpression, flow cytometry and in vivo zebrafish studies. Finally, the clinical relevance of these results was assessed using reported cohorts. (3) Results: We found that CSCs presented marked differences from the non-CSCs, including enrichment in transduction cascades related to stemness, cellular growth, proliferation and apoptosis. Interestingly, CSCs overexpressed a module of co-regulated Chromosomal Passenger Proteins including BIRC5 (survivin), INCENP and AURKB. Overexpression of BIRC5 increased the number of CSCs, as assessed by in vitro and in vivo zebrafish xenotransplant analyses. Analysis of previously published cohorts showed that this co-regulated module was not only overexpressed in basal breast tumors but also associated with relapse-free and overall survival in these patients. (4) Conclusions: These results underline the importance of Cancer Stem Cells in breast cancer progression and point toward the possible use of chromosomal passenger proteins as prognostic factors.

Asunto(s)

Neoplasias de la Mama/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Apoptosis , Aurora Quinasa B/genética , Aurora Quinasa B/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Proteínas Cromosómicas no Histona/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Células Madre Neoplásicas/patología , Pronóstico , Survivin/genética , Survivin/metabolismo , Pez Cebra

RESUMEN

Aurora B kinase has a critical role in regulating attachments between kinetochores and spindle microtubules during mitosis. Early in mitosis, kinase activity at kinetochores is high to promote attachment turnover, and in later mitosis, activity decreases to ensure attachment stabilization. Aurora B localizes prominently to inner centromeres, and a population of the kinase is also detected at kinetochores. How Aurora B is recruited to and evicted from these regions to regulate kinetochore-microtubule attachments remains unclear. Here, we identified and investigated discrete populations of Aurora B at the centromere/kinetochore region. An inner centromere pool is recruited by Haspin phosphorylation of histone H3, and a kinetochore-proximal outer centromere pool is recruited by Bub1 phosphorylation of histone H2A. Finally, a third pool resides ~20 nm outside of the inner kinetochore protein CENP-C in early mitosis and does not require either the Bub1/pH2A/Sgo1 or Haspin/pH3 pathway for localization or activity. Our results suggest that distinct molecular pathways are responsible for Aurora B recruitment to centromeres and kinetochores.

Asunto(s)

Aurora Quinasa B/metabolismo , Centrómero/enzimología , Cinetocoros/enzimología , Mitosis , Aurora Quinasa B/genética , Sitios de Unión , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Centrómero/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Células HeLa , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosforilación , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas , Transducción de Señal , Factores de Tiempo

RESUMEN

Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verified how thalidomide affect them in human pluripotent stem cells (hPSCs) through a differential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identified 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were significantly different (p < 0.05). Eleven variants in SALL4 and TBX5 were previously associated with cardiac diseases or malformations; however, in TE sample there was no association. Variant effect prediction tools showed 97% of the variants with potential to influence in these genes regulation. DGE analysis showed a significant reduction of ESCO2 in hPSCs after thalidomide exposure.

Asunto(s)

Acetiltransferasas/genética , Proteínas Cromosómicas no Histona/genética , Predisposición Genética a la Enfermedad , Proteínas de Dominio T Box/genética , Teratogénesis/genética , Talidomida/efectos adversos , Factores de Transcripción/genética , Anomalías Múltiples/inducido químicamente , Anomalías Múltiples/genética , Brasil , Línea Celular , Anomalías Craneofaciales/inducido químicamente , Anomalías Craneofaciales/genética , Conjuntos de Datos como Asunto , Síndrome de Retracción de Duane/inducido químicamente , Síndrome de Retracción de Duane/genética , Ectromelia/inducido químicamente , Ectromelia/genética , Femenino , Perfilación de la Expresión Génica , Frecuencia de los Genes , Cardiopatías Congénitas/inducido químicamente , Cardiopatías Congénitas/genética , Defectos del Tabique Interatrial/inducido químicamente , Defectos del Tabique Interatrial/genética , Humanos , Hipertelorismo/inducido químicamente , Hipertelorismo/genética , Lepra/tratamiento farmacológico , Deformidades Congénitas de las Extremidades Inferiores/inducido químicamente , Deformidades Congénitas de las Extremidades Inferiores/genética , Masculino , Mutación , Células Madre Pluripotentes , Polimorfismo de Nucleótido Simple , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Mapas de Interacción de Proteínas/genética , Teratogénesis/efectos de los fármacos , Deformidades Congénitas de las Extremidades Superiores/inducido químicamente , Deformidades Congénitas de las Extremidades Superiores/genética

RESUMEN

SWI/SNF or BAF chromatin-remodeling complexes are polymorphic assemblies of homologous subunit families that remodel nucleosomes and facilitate tissue-specific gene regulation during development. BAF57/SMARCE1 is a BAF complex subunit encoded in animals by a single gene and is a component of all mammalian BAF complexes. In vivo, the loss of SMARCE1 would lead to the formation of deficient combinations of the complex which might present limited remodeling activities. To address the specific contribution of SMARCE1 to the function of the BAF complex, we generated CRISPR/Cas9 mutations of smarce1 in zebrafish. Smarce1 mutants showed visible defects at 72 hpf, including smaller eyes, abnormal body curvature and heart abnormalities. Gene expression analysis revealed that the mutant embryos displayed defects in endocardial development since early stages, which led to the formation of a misshapen heart tube. The severe morphological and functional cardiac problems observed at 4 dpf were correlated with the substantially increased expression of different cardiac transcription factors. Additionally, we showed that Smarce1 binds to cis-regulatory regions of the gata5 gene and is necessary for the recruitment of the BAF complex to these regions.

Asunto(s)

Proteínas Cromosómicas no Histona , Endocardio/embriología , Regulación del Desarrollo de la Expresión Génica , Mutación , Factores de Transcripción , Proteínas de Pez Cebra , Pez Cebra , Animales , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Embrión no Mamífero/embriología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo

RESUMEN

Glioblastoma (GBM) is an incurable disease ranked among the deadliest solid cancers worldwide. A better understanding on the molecular aspects of this malignancy could contribute to the development of new treatment strategies and help to improve survival rates. Previously, our group had shown that GBM patients expressing the cancer/testis antigen Opa Interacting Protein 5 (OIP5) present a longer survival period than the OIP5-negative group. The main goal of this study was to evaluate the OIP5 contribution to GBM tumorigenesis and assess the role of OIP5 in GBM cell response to lomustine, an alkylating agent used in the treatment of this malignancy. So, the effect of OIP5 knockdown was evaluated in A172 and T98G GBM cell lines. Our results demonstrated that downregulation of the OIP5 stimulates glioma cell viability and inhibits cell death-induced necrosis prompted by lomustine. In conclusion, our data shows that OIP5 expression in GBM cells seems to be able to enhance lomustine cytotoxic effects, reinforcing that this gene is a potential therapeutic target and putative molecular biomarker for treatment response in GBM.

Asunto(s)

Neoplasias Encefálicas/metabolismo , Proteínas Cromosómicas no Histona/genética , Resistencia a Antineoplásicos/genética , Glioblastoma/metabolismo , Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proteínas Cromosómicas no Histona/metabolismo , Humanos , Lomustina/farmacología

RESUMEN

The heterochromatic genome compartment mediates strictly conserved cellular processes such as chromosome segregation, telomere integrity, and genome stability. Paradoxically, heterochromatic DNA sequence is wildly unconserved. Recent reports that many hybrid incompatibility genes encode heterochromatin proteins, together with the observation that interspecies hybrids suffer aberrant heterochromatin-dependent processes, suggest that heterochromatic DNA packaging requires species-specific innovations. Testing this model of coevolution between fast-evolving heterochromatic DNA and its packaging proteins begins with defining the latter. Here we describe many such candidates encoded by the Heterochromatin Protein 1 (HP1) gene family across Diptera, an insect Order that encompasses dramatic episodes of heterochromatic sequence turnover. Using BLAST, synteny analysis, and phylogenetic tree building across 64 Diptera genomes, we discovered a staggering 121 HP1 duplication events. In contrast, we observed virtually no gene duplication in gene families that share a common "chromodomain" with HP1s, including Polycomb and Su(var)3-9. The remarkably high number of Dipteran HP1 paralogs arises from distant clades undergoing convergent HP1 family amplifications. These independently derived, young HP1s span diverse ages, domain structures, and rates of molecular evolution, including episodes of positive selection. Moreover, independently derived HP1s exhibit convergent expression evolution. While ancient HP1 parent genes are transcribed ubiquitously, young HP1 paralogs are transcribed primarily in male germline tissue, a pattern typical of young genes. Pervasive gene youth, rapid evolution, and germline specialization implicate heterochromatin-encoded selfish elements driving recurrent HP1 gene family expansions. The 121 young genes offer valuable experimental traction for elucidating the germline processes shaped by Diptera's many dramatic episodes of heterochromatin turnover.

Asunto(s)

Proteínas Cromosómicas no Histona/genética , Dípteros/genética , Secuencia de Aminoácidos/genética , Animales , Evolución Biológica , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/fisiología , Evolución Molecular , Amplificación de Genes/genética , Duplicación de Gen/genética , Silenciador del Gen , Inestabilidad Genómica/genética , Heterocromatina/genética , Heterocromatina/fisiología , Filogenia , Telómero/metabolismo

RESUMEN

Breast and cervical cancer are the first and fourth cancer types with the highest prevalence in women, respectively. The developmental profiles of cancer in women can vary by genetic markers and cellular events. In turn, age and lifestyle influence in the cellular response and also on the cancer progression and relapse. The human DEK protein, a histone chaperone, belongs to a specific subclass of chromatin topology modulators, being involved in the regulation of DNA-dependent processes. These epigenetic mechanisms have dynamic and reversible nature, have been proposed as targets for different treatment approaches, especially in tumor therapy. The expression patterns of DEK vary between healthy and cancer cells. High expression of DEK is associated with poor prognosis in many cancer types, suggesting that DEK takes part in oncogenic activities via different molecular pathways, including inhibition of senescence and apoptosis. The focus of this review was to highlight the role of the DEK protein in these two female cancers.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Oncogénicas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Salud de la Mujer , Animales , Biomarcadores de Tumor/química , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/genética , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Oncogénicas/química , Proteínas Oncogénicas/genética , Proteínas de Unión a Poli-ADP-Ribosa/química , Proteínas de Unión a Poli-ADP-Ribosa/genética , Pronóstico , Conformación Proteica , Relación Estructura-Actividad , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapia

RESUMEN

OBJECTIVE: Spermatogenesis is a complex process controlled by a plethora of genes. Changes in expression and function of these genes may thus lead to spermatogenic deficiency and male infertility. TEX11, TEX12, TEX14 and TEX15 are germ cell-specific genes expressed in the testis. TEX11, involved in the initiation and maintenance of chromosome synapses in meiotic chromosomes, has been shown to be essential for meiosis and fertility in males. TEX14, a component of intercellular bridges in germ cells, is required for spermatogenesis and fertility. TEX12 and TEX15 are essential for correct assembly of the synaptonemal complex and thus meiosis progression. METHODS: In order to examine whether changes in expression of these genes is associated with impaired spermatogenesis, expression levels of these genes were quantified by RT-qPCR on samples retrieved from infertile patients submitted to diagnostic testicular biopsy at Royan institute. Samples were divided into two groups of 18 patients with non-obstructive azoospermia considered as case; nine patients with obstructive azoospermia were included in the control group. RESULTS: A significant down-regulation of these genes was observed in the SCOS group when compared to the control group. CONCLUSION: This result suggests that regular expression of TEX11, TEX12, TEX14 and TEX15 is essential for the early stages of spermatogenesis.

Asunto(s)

Azoospermia/genética , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Espermatogénesis/genética , Testículo/metabolismo , Factores de Transcripción/genética , Adulto , Azoospermia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Factores de Transcripción/metabolismo

RESUMEN

Despite their essential role in the process of chromosome segregation in eukaryotes, kinetochore proteins are highly diverse across species, being lost, duplicated, created, or diversified during evolution. Based on comparative genomics, the duplication of the inner kinetochore proteins CenH3 and Cenp-C, which are interdependent in their roles of establishing centromere identity and function, can be said to be rare in animals. Surprisingly, the Drosophila CenH3 homolog Cid underwent four independent duplication events during evolution. Particularly interesting are the highly diverged Cid1 and Cid5 paralogs of the Drosophila subgenus, which are probably present in over one thousand species. Given that CenH3 and Cenp-C likely co-evolve as a functional unit, we investigated the molecular evolution of Cenp-C in species of Drosophila. We report yet another Cid duplication (leading to Cid6) within the Drosophila subgenus and show that not only Cid, but also Cenp-C is duplicated in the entire subgenus. The Cenp-C paralogs, which we named Cenp-C1 and Cenp-C2, are highly divergent. Both Cenp-C1 and Cenp-C2 retain key motifs involved in centromere localization and function, while some functional motifs are conserved in an alternate manner between the paralogs. Interestingly, both Cid5 and Cenp-C2 are male germline-biased and evolved adaptively. However, it is currently unclear if the paralogs subfunctionalized or if the new copies acquired a new function. Our findings point towards a specific inner kinetochore composition in a specific context (i.e., spermatogenesis), which could prove valuable for the understanding of how the extensive kinetochore diversity is related to essential cellular functions.

Asunto(s)

Proteína A Centromérica/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Evolución Molecular , Duplicación de Gen , Genes de Insecto , Células Germinativas/metabolismo , Animales , Sesgo , Proteína A Centromérica/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas/genética , Proteínas de Drosophila/metabolismo , Funciones de Verosimilitud , Masculino , Filogenia

RESUMEN

Sunflecks, transient patches of light that penetrate through gaps in the canopy and transiently interrupt shade, are eco-physiologically and agriculturally important sources of energy for carbon gain, but our molecular understanding of how plant organs perceive and respond to sunflecks through photoreceptors remains limited. The UV-B photoreceptor UV RESISTANCE LOCUS8 (UVR8) is a recent addition to the list of plant photosensory receptors, and we have made considerable advances in our understanding of the physiology and molecular mechanisms of action of UVR8 and its signaling pathway. However, the function of UVR8 in the natural environment is poorly understood. Here, we show that the UVR8 dimer/monomer ratio responds quantitatively and reversibly to the intensity of sunflecks that interrupt shade in the field. Sunflecks reduced hypocotyl growth and increased CHALCONE SYNTHASE (CHS) and ELONGATED HYPOCOTYL5 gene expression and CHS protein abundance in wild-type Arabidopsis (Arabidopsis thaliana) seedlings, but the uvr8 mutant was impaired in these responses. UVR8 was also required for normal nuclear dynamics of CONSTITUTIVELY PHOTOMORPHOGENIC1. We propose that UVR8 plays an important role in the plant perception of and response to sunflecks.

Asunto(s)

Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiología , Proteínas Cromosómicas no Histona/metabolismo , Fotorreceptores de Plantas/metabolismo , Aciltransferasas/genética , Aciltransferasas/metabolismo , Proteínas de Arabidopsis/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Proteínas Cromosómicas no Histona/genética , Regulación de la Expresión Génica de las Plantas , Hipocótilo/crecimiento & desarrollo , Luz , Mutación , Proteínas Nucleares/genética , Fotorreceptores de Plantas/genética , Tallos de la Planta/crecimiento & desarrollo , Plantas Modificadas Genéticamente , Transducción de Señal/fisiología , Rayos Ultravioleta

RESUMEN

Confocal and electron microscopy images, and WB analysis of cellular fractions revealed that HP1γ is in the nucleus but also in the cytoplasm of C2C12 myoblasts, myotubes, skeletal and cardiac muscles, N2a, HeLa and HEK293T cells. Signal specificity was tested with different antibodies and by HP1γ knockdown. Leptomycin B treatment of myoblasts increased nuclear HP1γ, suggesting that its nuclear export is Crm-1-dependent. HP1γ exhibited a filamentous pattern of staining partially co-localizing with actin in the cytoplasm of myotubes and myofibrils. Immunoelectron microscopic analysis showed high-density immunogold particles that correspond to HP1γ localized to the Z-disk and A-band of the sarcomere of skeletal muscle. HP1γ partially co-localized with actin in C2C12 myotubes and murine myofibrils. Importantly, actin co-immunoprecipitated with HP1γ in the nuclear and cytosolic fractions of myoblasts. Actin co-immunoprecipitated with HP1γ in myoblasts incubated in the absence or presence of the actin depolymerizing agent cytochalasin D, suggesting that HP1γ may interact with G-and F-actin. In the cytoplasm, HP1γ was associated to the perinuclear actin cap that controls nuclear shape and position. In the nucleus, re-ChIP assays showed that HP1γ-actin associates to the promoter and transcribed regions of the house keeping gene GAPDH, suggesting that HP1γ may function as a scaffold protein for the recruitment of actin to control gene expression. When HP1γ was knocked-down, myoblasts were unable to differentiate or originated thin myotubes. In summary, HP1γ is present in the nucleus and the cytoplasm interacting with actin, a protein complex that may exert different functions depending on its subcellular localization.

Asunto(s)

Diferenciación Celular , Núcleo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Citoplasma/metabolismo , Mioblastos Cardíacos/metabolismo , Mioblastos Esqueléticos/metabolismo , Actinas/genética , Actinas/metabolismo , Animales , Núcleo Celular/genética , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/genética , Citoplasma/genética , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Ratones , Mioblastos Cardíacos/citología , Mioblastos Esqueléticos/citología

RESUMEN

Biological rhythms can be defined as changes in physiological or behavioral variables that repeat at certain time intervals. Rhythms that last approximately 24 h are referred to as circadian rhythms. Modern lifestyles have drastically affected human habits, as well as the population's eating habits. These changes have generated an epidemic of metabolic syndromes, such as obesity and diabetes. In an attempt to combat obesity, populations have attempted to use many different herbal remedies and plant-based drugs, the most common of which is Camellia sinensis, or green tea. Most of the studies on the effects of C. sinensis on maintaining body weight have reported the involvement of this substance in lipid oxidation. The objective of this study was to evaluate how the administration of C. sinensis at different times of day influenced changes in body weight, blood glucose levels, and food intake of mice kept under different diet conditions. The structural organization of abdominal adipose tissue was also evaluated, as were certain aspects of lipid metabolism and overall synthetic activity in the liver, adipose tissue, and ovaries. The results obtained suggest that the intake of green tea in the light phase of the day stimulates weight loss, regardless of the diet ingested. Neither glucose levels nor the structural organization of adipose tissue was found to be altered in any of the experimental groups. Neither diet nor the time at which the green tea was administered was found to have any effects on the amount of food the mice consumed. The time at which green tea was consumed and the type of diet both influenced LXRαß nuclear receptor expression, as well as the expression of fibrillarin in the liver and ovaries, although this influence was tissue specific.

Asunto(s)

Antioxidantes/farmacología , Ritmo Circadiano/efectos de los fármacos , Dieta , Homeostasis , Metabolismo de los Lípidos/efectos de los fármacos , Extractos Vegetales/farmacología , Té , Tejido Adiposo/efectos de los fármacos , Animales , Antioxidantes/administración & dosificación , Peso Corporal/efectos de los fármacos , Camellia sinensis/química , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Cronoterapia/métodos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Hígado/metabolismo , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Ratones , Ovario/metabolismo , Oxidación-Reducción , Extractos Vegetales/administración & dosificación