ABSTRACT
BACKGROUND Imitation SWItch (ISWI) ATPase is the catalytic subunit in diverse chromatin remodeling complexes. These complexes modify histone-DNA interactions and therefore play a pivotal role in different DNA-dependent processes. In Trypanosoma cruzi, a protozoan that controls gene expression principally post-transcriptionally, the transcriptional regulation mechanisms mediated by chromatin remodeling are poorly understood. OBJECTIVE To characterise the ISWI remodeler in T. cruzi (TcISWI). METHODS A new version of pTcGW vectors was constructed to express green fluorescent protein (GFP)-tagged TcISWI. CRISPR-Cas9 system was used to obtain parasites with inactivated TcISWI gene and we determined TcISWI partners by cryomilling-affinity purification-mass spectrometry (MS) assay as an approximation to start to unravel the function of this protein. FINDINGS Our approach identified known ISWI partners [nucleoplasmin-like protein (NLP), regulator of chromosome condensation 1-like protein (RCCP) and phenylalanine/tyrosine-rich protein (FYRP)], previously characterised in T. brucei, and new components in TcISWI complex [DRBD2, DHH1 and proteins containing a domain characteristic of structural maintenance of chromosomes (SMC) proteins]. Data are available via ProteomeXchange with identifier PXD017869. MAIN CONCLUSIONS In addition to its participation in transcriptional silencing, as it was reported in T. brucei, the data generated here provide a framework that suggests a role for TcISWI chromatin remodeler in different nuclear processes in T. cruzi, including mRNA nuclear export control and chromatin compaction. Further work is necessary to clarify the TcISWI functional diversity that arises from this protein interaction study.
Subject(s)
Animals , Transcription Factors/genetics , Trypanosoma cruzi/genetics , Adenosine Triphosphatases/genetics , Chromatin Assembly and Disassembly/genetics , Gene Expression Regulation , Blotting, Western , Flow CytometryABSTRACT
Cuando hablamos de epigenética nos referimos a los fenómenos que regulan la expresión génica sin afectar la secuencia del ADN. La epigénesis representa, en definitiva, un mecanismo para el almacenamiento de información. Las consecuencias a largo plazo de las experiencias ambientales tempranas en el desarrollo han sido extensamente exploradas en modelos animales. Estos cambios neuroquímicos y comportamentales se hallan estrechamente vinculados a mecanismos epigenéticos. En este artículo se revisa la evidencia sobre la influencia en el epigenoma de la interacción ambiente-gen y las implicancias de tales efectos epigenéticos sobre la salud mental humana. La comprensión del concepto epigénesis, entonces, nos permite conceptualizar, evaluar, prevenir e intervenir tanto de manera farmacológica como no farmacológica en las enfermedades psiquiátricas e interrumpir la transmisión de ciertas patologías a través de las generaciones.
Epigenetics refers to the phenomena regulating gene expression without affecting the DNA sequence. Epigenetics, therefore, represents a mechanism for the storage of information. The long-term effects of early environmental experiences on development have been widely assessed in animal models. These neurochemical and behavioral changes are closely connected with epigenetic mechanisms. This article provides a review of the evidence concerning the influence of the gene-environment interaction on the epigenome, as well as the implications of such epigenetic effects for human mental health. Understanding the concept of epigenetics, therefore, allows us to conceptualize, evaluate, prevent and to intervene both pharmacologically and not pharmacologically in psychiatric diseases, as well as to stop the transmission of certain pathologies accross generations.
Subject(s)
Humans , Epigenesis, Genetic , Chromatin Assembly and Disassembly/genetics , Gene Expression , Histone Code , Mental Health , Psychiatry , RNA InterferenceABSTRACT
En una elevada proporción de casos de leucemias de nuevo diagnóstico se detectan genes de fusión, los cuales frecuentemente presentan secuencias codificadoras de factores de transcripción. Se ha demostrado que algunas proteínas de fusión como Pml-Rarα inhiben la diferenciación celular, al reclutar complejos correpresores nucleares que mantienen una actividad de histona desacetilasa (HDAC en inglés) sobre promotores de genes específicos importantes en diferenciación de una determinada estirpe celular. Esta represión transcripcional dependiente de HDAC representa una vía común en el desarrollo de leucemia y por lo tanto puede ser un blanco importante de nuevos compuestos terapéuticos. Por otro lado, la oncoproteína Bcr-Abl muestra una alta actividad de tirosina-cinasa, la cual desregula vías de transducción de señales involucradas normalmente en proliferación y apoptosis. Esta actividad aberrante puede ser afectada por inhibidores de transducción de señales (STIs, del inglés), los cuales bloquean la ruta oncogénica y representan un gran avance terapéutico. En esta revisión analizamos con cierto detalle lo que se conoce en la actualidad sobre la represión transcripcional reversible controlada por HDAC y sobre la transducción de señales aumentada por Bcr-Abl. Adicionalmente indicamos que la aplicación de fármacos de bajo peso molecular para el control de las leucemias humanas, basada en el conocimiento de los mecanismos moleculares de la enfermedad, lleva a una remisión clínica, con bajo riesgo de efectos tóxicos secundarios, lo cual está aumentando la mejoría de una alta proporción de los enfermos.
Leukemia-associated fusion genes are detected in a significant proportion of newly diagnosed cases, where genes encoding transcription factors are usually found at one of the breakpoints. Activated fusion proteins such as Pml-Raralpha have been shown to inhibit cellular differentiation by recruitment of nuclear corepressor complexes, which maintain local histone deacetylase (HDAC) in a variety of hematologic lineage-specific gene promoters. This HDAC-dependent transcriptional repression appears as a common pathway in the development of leukemia and could constitute an important target for new therapeutic agents. Alternatively, the Bcr-Abl oncoprotein shows high tyrosine kinase activity and deregulates signal transduction pathways normally involved in both apoptosis and proliferation. This aberrant activity is affected by signal transduction inhibitors (STIs), which block or prevent the oncogenic pathway. In this review, we shed some light on our understanding of both the reversible transcriptional repression controlled by HDAC and the deregulated Bcr-Abl signal transduction pathway. In addition, the administration of low molecular weight drugs for human leukemia treatment based on this knowledge brings about a significant long-term clinical remission and an acceptable risk of toxic effects that should increase the cure rate.