Search results for "epigenetics"

Characterization of the pleiotropic LysR-type transcription regulator LeuO of Escherichia coli

2019

AbstractLeuO is a pleiotropic LysR-type transcriptional regulator (LTTR) and co-regulator of the abundant nucleoid-associated repressor protein H-NS in Gammaproteobacteria. As other LTTRs, LeuO is a tetramer that is formed by dimerization of the N-terminal DNA-binding domain (DBD) and C-terminal effector-binding domain (EBD). To characterize the Escherichia coli LeuO protein, we screened for LeuO mutants that activate the cas (CRISPR-associated/Cascade) promoter more effectively than wild-type LeuO. This yielded nine mutants carrying amino acid substitutions in the dimerization interface of the regulatory EBD, as shown by solving the EBD’s crystal structure. Superimposing of the crystal str…

Novel antiproliferative chimeric compounds with marked histone deacetylase inhibitory activity.

2014

Given our interest in finding potential antitumor agents and in view of the multifactorial mechanistic nature of cancer, in the present work, taking advantage of the multifunctional ligands approach, new chimeric molecules were designed and synthesized by combining in single chemical entities structural features of SAHA, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives previously obtained by us and endowed with antiproliferative and pro-apoptotic activity. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on different tumor cell lines, as well as their HDACs inhibitio…

FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis.

2013

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy with a strong epigenetic component. It is associated with deletion of a macrosatellite repeat leading to over-expression of the nearby genes. Among them, we focused on FSHD region gene 1 (FRG1) since its over-expression in mice, Xenopus laevis and Caenorhabditis elegans, leads to muscular dystrophy-like defects, suggesting that FRG1 plays a relevant role in muscle biology. Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. Moreov…

Phf21b imprints the spatiotemporal epigenetic switch essential for neural stem cell differentiation.

2019

Cerebral cortical development in mammals involves a highly complex and organized set of events including the transition of neural stem and progenitor cells (NSCs) from proliferative to differentiative divisions to generate neurons. Despite progress, the spatiotemporal regulation of this proliferation-differentiation switch during neurogenesis and the upstream epigenetic triggers remain poorly known. Here we report a cortex-specific PHD finger protein, Phf21b, which is highly expressed in the neurogenic phase of cortical development and gets induced as NSCs begin to differentiate. Depletion of Phf21b in vivo inhibited neuronal differentiation as cortical progenitors lacking Phf21b were retai…

Role of TET3 in the epigenetic regulation of neural stemness maintenance

2018

Las células madre neurales adultas (NSCs) son capaces de autorrenovarse ilimitadamente mientras mantienen su capacidad de diferenciarse. Desde su descubrimiento, las NSCs se han estudiado extensamente y el campo se mantiene en continuo progreso. La SVZ es el principal nicho neurogénico en ratones en el que la neurogénesis se produce continuamente durante toda la vida. Para explorar el posible uso terapéutico de estas células, el conocimiento de su regulación es esencial. Diversas evidencias sugieren que los mecanismos epigenéticos como la metilación del ADN, las modificaciones de histonas y la impronta genómica pueden interactuar con factores transcripcionales y ambientales en NSCs moduland…

Two independent epigenetic biomarkers predict survival in neuroblastoma.

2015

Background Neuroblastoma (NB) is the most common extracranial pediatric solid tumor with a highly variable clinical course, ranging from spontaneous regression to life-threatening disease. Survival rates for high-risk NB patients remain disappointingly low despite multimodal treatment. Thus, there is an urgent clinical need for additional biomarkers to improve risk stratification, treatment management, and survival rates in children with aggressive NB. Results Using gene promoter methylation analysis in 48 neuroblastoma tumors with microarray technology, we found a strong association between survival and gene promoter hypermethylation (P = 0.036). Hypermethylation of 70 genes significantly …

A “Lymphocyte MicroRNA Signature” as Predictive Biomarker of Immunotherapy Response and Plasma PD-1/PD-L1 Expression Levels in Patients with Metastat…

2020

Introduction of checkpoint inhibitors resulted in durable responses and improvements in overall survival in advanced RCC patients, but the treatment efficacy is widely variable, and a considerable number of patients are resistant to PD-1/PD-L1 inhibition. This variability of clinical response makes necessary the discovery of predictive biomarkers for patient selection. Previous findings showed that the epigenetic modifications, including an extensive microRNA-mediated regulation of tumor suppressor genes, are key features of RCC. Based on this biological background, we hypothesized that a miRNA expression profile directly identified in the peripheral lymphocytes of the patients before and a…

Circulating miRNAs in Successful and Unsuccessful Aging. A Mini-review

2019

Aging is a multifactorial process that affects the organisms at genetic, molecular and cellular levels. This process modifies several tissues with a negative impact on cells physiology, tissues and organs functionality, altering their regeneration capacity. The chronic low-grade inflammation typical of aging, defined as inflammaging, is a common biological factor responsible for the decline and beginning of the disease in age. A murine parabiosis model that combines the vascular system of old and young animals, suggests that soluble factors released by young individuals may improve the regenerative potential of old tissue. Therefore, circulating factors have a key role in the induction of …

Epigenetics in Brain Development and Disease

2017

Validation of microRNA expression profile in Oral Lichenoid Disease through cytological samples

2019

Background To validate oral exfoliative cytology in the analysis of the microRNA expression profile in Oral Lichenoid Disease (OLD).